WO2018004066A1 - Novel aryl ethane derivative and pharmaceutical composition containing same as active ingredient - Google Patents

Novel aryl ethane derivative and pharmaceutical composition containing same as active ingredient Download PDF

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WO2018004066A1
WO2018004066A1 PCT/KR2016/010369 KR2016010369W WO2018004066A1 WO 2018004066 A1 WO2018004066 A1 WO 2018004066A1 KR 2016010369 W KR2016010369 W KR 2016010369W WO 2018004066 A1 WO2018004066 A1 WO 2018004066A1
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Prior art keywords
alkyl
heterocycloalkyl
hydroxy
heteroaryl
formula
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PCT/KR2016/010369
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French (fr)
Korean (ko)
Inventor
황성연
조성진
김진아
진정욱
황하영
이인규
전용현
이재태
전재한
김상욱
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주식회사한국전통의학연구소
황성연
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Priority claimed from KR1020160080124A external-priority patent/KR101819639B1/en
Priority claimed from KR1020160117200A external-priority patent/KR101835133B1/en
Application filed by 주식회사한국전통의학연구소, 황성연 filed Critical 주식회사한국전통의학연구소
Priority to ES16907431T priority Critical patent/ES2919557T3/en
Priority to CN201680087227.1A priority patent/CN109563054B/en
Priority to EP16907431.7A priority patent/EP3459936B1/en
Priority to US16/313,360 priority patent/US20190167820A1/en
Publication of WO2018004066A1 publication Critical patent/WO2018004066A1/en
Priority to US16/677,596 priority patent/US11285226B2/en

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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines

Definitions

  • the present invention relates to arylethene derivatives that inhibit the activity of Estrogen related receptor gamma (hereinafter referred to as 'ERR ⁇ '), prodrugs thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof; and It relates to a pharmaceutical composition containing this as an active ingredient.
  • Estrogen related receptor gamma hereinafter referred to as 'ERR ⁇ '
  • hormone receptors that respond to hormones are required.
  • cell membrane receptors and nuclear receptors There are largely cell membrane receptors and nuclear receptors. Among them, there is a growing interest in orphan nuclear receptors (Orphan Nuclear Receptor), the ligand that binds to the nuclear receptor is not known.
  • ERR ⁇ ERR ⁇
  • ERR ⁇ ERR ⁇
  • ERR ⁇ Eestrogen Related Receptor
  • ERR ⁇ is a transcriptional regulatory protein that is active in the spinal cord and central nervous system, and is involved in glucose biosynthesis in the liver. It is a nuclear hormone receptor that helps to express glucose synthesis-related genes by binding to ligands. In other words, ERR ⁇ is directly involved in glucose metabolism.
  • ERR ⁇ is a human nuclear receptor protein called NR3B3, which is encoded by the ESRRG gene. ERR ⁇ functions as a constitutive activator in transcription. ERR ⁇ is a member of the nuclear hormone receptor family of steroid hormone receptors.
  • the ERR ⁇ protein has been known as a major regulator of various genes involved in fatty acid oxidation and mitochondrial biogeneration in the myocardium, and is also known to be involved in glucose production in the liver.
  • diabetic retinopathy is a disease caused by a specific retinal circulation disorder in diabetic patients and is one of three major microvascular complications in diabetes along with diabetic neuropathy and diabetic nephropathy.
  • the incidence of diabetic retinopathy has been linked to the prevalence of diabetes mellitus. For diabetics diagnosed before age 30, type 1, 17% when the disease is under 5 years and 98% when the disease is 15 years or more. Among these, worsening proliferative diabetic retinopathy occurs in about 1% of patients under 10 years of age and 67% of patients over 35 years of age.
  • diabetic retinopathy In type 2 diabetes, 29% of patients are younger than 5 years, 78% of patients are older than 15 years, and proliferative diabetic retinopathy is reported in 2% of patients younger than 5 years and 16% of patients over 15 years.
  • diabetic retina changes in blood vessels in capillaries such as thickening of retinal capillary basement membrane, loss of perivascular cells, and microvascular perfusion occur. Over time, retinal neovascularization also occurs after extensive capillary nonperfusion. It is known that it can.
  • diabetic retinopathy is a type of diabetic complication, once developed, it is difficult to prevent its progression due to blood sugar control, and a specific treatment method for retinopathy is required.
  • GSK5182 which is (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol It has been reported that a small molecule organic compound known as a ligand acts as a ligand to ERR ⁇ and inhibits the activity of ERR ⁇ , thereby exhibiting antidiabetic effects such as relieving hyperglycemia and insulin resistance and treating retinopathy.
  • Anaplastic thyroid cancer on the other hand, is one of the most aggressive and deadly cancers known to occur in humans. ATC rapidly metastasizes from the thyroid gland to the lungs, bones, regional lymph nodes, and brain. This contrasts with the nature of well-differentiated benign thyroid cancers, which account for most thyroid cancers, and therefore, treatment of ATC alone or in combination with surgery, radiation therapy, and chemotherapy has not been effective in patient survival. . As a result, the development of new treatment methods is urgently needed.
  • NIS Sodium iodide symporter
  • ERR ⁇ Biological effects of ERR ⁇ have been linked to various disease models (some metabolic diseases such as type 2 diabetes mellitus, alcohol-induced oxidative stress, liver damage and microbial infection through damaged gluconeogenesis, liver insulin signaling, and iron metabolism). has been studied extensively, but the role of ERR ⁇ on NIS function in ATC has not been clearly studied to date.
  • GSK5182 which is (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol It has been reported that a small molecule organic compound known as a ligand acts as a ligand to ERR ⁇ , thereby inhibiting ERR ⁇ activity, thereby improving NIS function, increasing radioactive iodine intake in ATC cells, and finally increasing radioiodine treatment.
  • administration of GSK5182 to the ATC mouse tumor model did not result in increased tumor iodine uptake. Therefore, compared with GSK5182, it is possible to specifically inhibit ERR ⁇ transcriptional activity, and as a result, it is required to develop a new substance that can cause an increase in radioisotope intake from the cellular level to the animal level.
  • the inventors of the present invention found that the introduction of specific substituents on the arylethene derivatives resulted in more excellent inhibitory activity of ERR ⁇ and improved drug stability, pharmacological activity and toxicity compared to the conventionally reported GSK5182. It was.
  • Another object of the present invention is a pharmaceutical for the prophylaxis or treatment of a disease mediated by ERR ⁇ containing the arylethene derivative, its prodrug, solvate, stereoisomer or pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a composition.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating retinopathy, containing the arylethene derivative, prodrug thereof, solvate thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as an active ingredient. It is.
  • Still another object of the present invention includes the above arylethene derivatives, their prodrugs, their solvates, their stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and used in combination with radioactive iodine It is to provide a pharmaceutical composition for treating thyroid cancer.
  • Still another object of the present invention is to provide a kit for treating thyroid cancer comprising the arylethene derivative, its prodrug, its solvate, its stereoisomer or pharmaceutically acceptable salt thereof, and radioactive iodine.
  • the present invention is a novel compound that can effectively inhibit the activity of ERR ⁇ , an arylethene derivative represented by the following formula (1), prodrug thereof, solvate thereof, stereoisomer or pharmaceutical Provide acceptable salts thereof:
  • L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
  • R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
  • R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl
  • R 16 and R 17 are each independently (C 1 -C 20) alkyl
  • n is an integer from 1 to 3;
  • n is an integer of 0 or 1;
  • Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
  • R 21 and R 22 are each independently hydrogen, (C1-C20) alkylsulfonyl or (C3-C20) cycloalkylsulfonyl;
  • R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
  • R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
  • Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
  • the heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
  • the present invention by confirming the excellent ERR ⁇ inhibitory activity against the aryl ethene derivative represented by the formula (1), the aryl ethene derivative, its prodrug, solvate, stereoisomer or pharmaceutically acceptable salt thereof It provides a pharmaceutical composition for the prevention or treatment of diseases mediated by ERR ⁇ containing as an active ingredient.
  • the present invention is a retinopathy containing an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient capable of effectively inhibiting the activity of ERR ⁇ . It provides a pharmaceutical composition for the prophylaxis or treatment of.
  • the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, which can specifically inhibit ERR ⁇ transcriptional activity, and a pharmaceutical It provides a pharmaceutical composition for the treatment of thyroid cancer, comprising a carrier which can be used as is, and used in combination with radioactive iodine.
  • the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a radioactive iodine which can specifically inhibit ERR ⁇ transcriptional activity. It provides a kit for treating thyroid cancer.
  • the arylethene derivative of the present invention is a novel compound, which shows very high inhibitory activity against ERR ⁇ as well as improved drug stability, pharmacological activity and toxicity compared to the existing GSK5182 compound, and thus mediated by ERR ⁇ .
  • ERR ⁇ enzyme-mediated retinopathy
  • the arylethene derivatives of the present invention can specifically inhibit ERR ⁇ transcriptional activity significantly remarkably compared to GSK5182, and as a result, can increase radioisotope uptake from the cellular level to the animal level. Therefore, it is possible to significantly increase the therapeutic effect of radioactive iodine therapy for the treatment of cancer, and to effectively manufacture cancer cells with enhanced sodium iodide symporter (NIS) function when administered to cancer cells, and to apply them to related studies and clinical applications for the treatment of undifferentiated thyroid cancer. There is an excellent effect that can be made easier.
  • NIS sodium iodide symporter
  • 1 to 3 show the effect of compound 18a on radioactive iodine intake in undifferentiated thyroid cancer cells.
  • 6 and 7 show the effect of compound 18a on the regulation of endogenous ERR ⁇ protein expression in undifferentiated thyroid cancer cells.
  • 16 and 17 show the increased cytotoxicity of 131 I increased after treatment with Compound 18a on undifferentiated thyroid cancer cells.
  • 18-22 show the effect of compound 18a on radioiodine intake by administration of compound 18a in an ATC tumor model.
  • the present invention provides arylethene derivatives represented by Formula 1 below, prodrugs thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
  • R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
  • R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl
  • R 16 and R 17 are each independently (C 1 -C 20) alkyl
  • n is an integer from 1 to 3;
  • n is an integer of 0 or 1;
  • Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
  • R 21 and R 22 are each independently hydrogen, (C1-C20) alkylsulfonyl or (C3-C20) cycloalkylsulfonyl;
  • R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
  • R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
  • Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
  • the heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
  • the arylethene derivatives of the general formula (1) according to the present invention are novel compounds, which have very high inhibitory activity against ERR ⁇ and are particularly effective for the diseases mediated by ERR ⁇ , especially metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver or arteriosclerosis. In addition to being useful as a therapeutic and prophylactic agent, it can be used as an active ingredient in preventing or treating retinopathy.
  • the arylethene derivative of Formula 1 regulates MAP kinase (mitogen-activated protein kinase) by regulating the expression of endogenous ERR ⁇ protein, and improves the function of sodium iodide symporter (NIS).
  • MAP kinase mitogen-activated protein kinase
  • NIS sodium iodide symporter
  • alkyl refers to a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, examples of which alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl , Pentyl, hexyl, octyl, nonyl, and the like.
  • aryl of the present invention is an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by one hydrogen removal, each ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.
  • heteroaryl means a heteroaromatic monovalent radical which is an aryl group containing 1 to 4 heteroatoms selected from N, O and S as an aromatic ring skeleton atom and the remaining aromatic ring skeleton atoms are carbons. 5 to 6 membered monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated.
  • heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected by a single bond.
  • heteroaryl groups include pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzoimidazolyl, iso Oxazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, and the like.
  • arylene and “heteroarylene” mean divalent radicals of aromatic rings and heteroaromatic rings.
  • fused heterocycle refers to a divalent radical of a fused ring in which an aromatic ring is fused with a non-aromatic heterocycle including 1 to 4 heteroatoms selected from N, O, and S. It has a carbon atom or a nitrogen atom in a ring as a bonding site.
  • fused heterocycle include, but are not limited to, indolin, dihydrobenzofuran, dihydrobenzothiophene, and the like.
  • heterocycloalkyl refers to a monovalent radical of a non-aromatic heterocycle including 1 to 4 heteroatoms selected from N, O and S, wherein the non-aromatic heterocycle is a saturated or unsaturated monocyclic ring, It includes both polycyclic or spirochroic forms and can be linked via heteroatoms or carbon atoms.
  • heterocycloalkyl radicals examples include aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo [3.1.0] hexane, octahydro Monovalent radicals of non-aromatic heterocycles such as pyrrolo [3,4-c] pyrrole, 2,7-diazaspiro [4.4] nonane, 2-azaspiro [4.4] nonane and the like.
  • halo or halogen in the present invention means fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl of the present invention means alkyl substituted with one or more halogens, and examples thereof include trifluoromethyl and the like.
  • alkenyl of the present invention is a straight chain or branched unsaturated hydrocarbon monovalent radical comprising one or more double bonds between two or more carbon atoms, specifically, ethenyl, propenyl, prop-1-ene- 2 days, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl -2-butenyl and the like.
  • alkoxy in the present invention means an —O-alkyl radical, where “alkyl” is as defined above.
  • alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.
  • alkylcarbonyloxy refers to an —OC ( ⁇ O) alkyl radical, where “alkyl” is as defined above.
  • alkylcarbonyloxy radicals include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy and the like. But it is not limited thereto.
  • alkylcarbonylamino in the present invention means an —NHC ( ⁇ O) alkyl radical, where “alkyl” is as defined above.
  • alkylcarbonylamino radicals include methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, propylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, t-butylcarbonylamino, and the like. But it is not limited thereto.
  • alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, and the like. It is not limited.
  • cycloalkyl means a monovalent saturated carbocyclic radical composed of one or more rings.
  • examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • alkylsulfonyl in the present invention means an -SO 2 -alkyl radical, where 'alkyl' is as defined above.
  • alkylsulfonyl radicals include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
  • cycloalkylsulfonyl in the present invention means an —SO 2 -cycloalkyl radical, where 'cycloalkyl' is as defined above.
  • examples of such cycloalkylsulfonyl radicals include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and the like.
  • alkylsulfonyloxy in the present invention means an -OSO 2 -alkyl radical, where 'alkyl' is as defined above.
  • alkylsulfonyloxy radicals include, but are not limited to, methylsulfonyloxy, ethylsulfonyloxy, and the like.
  • hydroxyalkyl in the present invention means alkyl substituted with one or more hydroxy, and examples thereof include hydroxymethyl and the like.
  • the arylethene derivative may be represented by the following Chemical Formulas 2 to 5:
  • R 1 is (C3-C10) heterocycloalkyl, (C3-C10) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
  • R 11 to R 15 are each independently (C 3 -C 10) heterocycloalkyl;
  • R 16 and R 17 are each independently (C 1 -C 10) alkyl;
  • m is an integer from 1 to 3;
  • n is an integer of 0 or 1;
  • Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-
  • R 1 is (C3-C10) heterocycloalkyl or -O- (CH 2 ) m -R 11
  • R 11 is (C3-C10) Heterocycloalkyl
  • m is an integer from 1 to 3, wherein the heterocycloalkyl of R 1 and R 11 is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino (amidino), (C1-C10) alkoxycarbonyl, hydroxy (C1-C10) alkyl and di (C1-C10) alkylamino (C1-C10) alkyl, and may be further substituted with one or more selected from the group consisting of .
  • heterocycloalkyl of R 1 and R 11 to R 15 may be each independently selected from the following structures:
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  • the arylethene derivative may be more preferably represented by the following Formula 6:
  • R 1 is (C3-C10) heterocycloalkyl or —O— (CH 2 ) m —R 11 ;
  • R 11 is (C3-C10) heterocycloalkyl
  • n is an integer from 1 to 3;
  • the heterocycloalkyl of R 1 and R 11 is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, hydroxide May be further substituted with one or more selected from the group consisting of oxy (C 1 -C 10) alkyl and di (C 1 -C 10) alkylamino (C 1 -C 10) alkyl;
  • Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10 Alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1-C10) alkyl Carbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyloxy or (C3 -C10) cycloalkylsulfonyloxy and
  • R 2 is hydroxy, fluorine, (C 1 -C 10) alkylcarbonyloxy or (C 1 -C 10) alkylsulfonyloxy.
  • R 1 and R 11 may be heterocycloalkyl independently selected from the following structures:
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  • Ar is (C6-C12) aryl
  • aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1 -C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyl It may be further substituted with one or more selected from the group consisting of oxy or (C3
  • R 2 may be hydroxy
  • R 2 is hydroxy and R 1 may be heterocycloalkyl selected from the following structures:
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  • R 2 is hydroxy
  • R 1 is -O- (CH 2 ) m -R 11
  • m is an integer of 1 or 2
  • R 11 may be heterocycloalkyl selected from the following structures:
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl or hydroxy (C 1 -C 10) alkyl; L is O or S.
  • Ar is (C6-C12) aryl
  • aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1- C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) Amino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10 ) Alkylsulfonyloxy or (C3-C10) cycloalkylsul
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  • Ar is (C6-C12) aryl
  • aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1- C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) Amino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10 ) Alkylsulfonyloxy or (C3-C10) cycloalkylsul
  • R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl or hydroxy (C 1 -C 10) alkyl; L is O or S.
  • the arylethene derivative may be specifically selected from the following structures, but is not limited thereto.
  • the arylethene derivative may be preferably selected from the following structures.
  • the arylethene derivative may be more preferably selected from the following structures.
  • the arylethene derivative may be even more preferably selected from the following structures.
  • the arylethene derivatives according to the present invention can be used in the form of prodrugs, solvates and pharmaceutically acceptable salts to enhance in vivo absorption or increase solubility, so that the above prodrugs, solvates and pharmaceuticals Salts which are also acceptable are also within the scope of the present invention.
  • the arylethene derivative has a chiral carbon, so that stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.
  • the arylethene derivatives according to the present invention may be prepared by various methods known according to the type of substituents thereof.
  • the following Reaction Schemes 1 to 21 are exemplified. It does not limit the method. Further details are described in Examples 1 to 121 below. It will be apparent to those skilled in the art that the preparation methods shown in Schemes 1 to 21 are merely exemplary and can be easily modified by those skilled in the art according to specific substituents.
  • the present invention also provides an ERR ⁇ inhibitor composition
  • an ERR ⁇ inhibitor composition comprising an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention includes an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and further includes a pharmaceutically acceptable carrier. It provides a pharmaceutical composition for the prevention or treatment of diseases mediated by ERR ⁇ .
  • the arylethene derivatives of formula (1), their prodrugs, their solvates, their stereoisomers or their pharmaceutically acceptable salts exhibit high inhibitory activity against ERR ⁇ , and therefore, as an active ingredient
  • the pharmaceutical composition may be usefully used for the treatment or prevention of ERR ⁇ -mediated diseases such as obesity, diabetes, hyperlipidemia, fatty liver or atherosclerosis.
  • the present invention is a retinopathy containing an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient capable of effectively inhibiting the activity of ERR ⁇ . It provides a pharmaceutical composition for the prophylaxis or treatment of.
  • retinopathy is a disease caused by chronic or acute damage to the retina of the eye. Such retinopathy may involve ongoing inflammation and vascular remodeling. Retinopathy also manifests itself as a visual manifestation of systemic diseases such as diabetes or hypertension. Types of retinopathy include diabetic retinopathy and retinopathy of prematurity (ROP).
  • ROP retinopathy of prematurity
  • diabetic retinopathy refers to a complication of eyes in which a disorder occurs due to peripheral circulation disorder caused by systemic diabetes mellitus, resulting in decreased vision.
  • Diabetic retinopathy is initially asymptomatic, but the macular invasion develops, resulting in decreased vision.
  • Diabetic retinopathy is accompanied by various pathological features such as microvascular perfusion, venous dilatation, retinal hemorrhage, retinal infarction, macular edema, neovascularization, vitreous hemorrhage, and tractional membrane. Diagnosed.
  • Diabetic retinopathy is a disease that is caused by a combination of various symptoms as described above, and it is unclear whether treatment of the disease can be caused by being able to alleviate one of these symptoms.
  • prematurity retinopathy is a proliferative retinopathy that can occur in premature infants, especially underweight babies.
  • premature infants whose blood vessels are not fully formed at birth abnormal blood vessel proliferation occurs at the boundary between the retinal angiogenesis site and the angiogenesis site, resulting in abnormal retinal detachment. May result.
  • the arylethene derivatives according to the present invention can be used in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salts can be prepared by conventional methods in the art, for example hydrochloric acid, bromic acid.
  • Salts with inorganic acids such as sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, mandelic acid, cinnamic acid Salts with organic acids such as stearic acid, palmitic acid, glycolic acid, glutamic acid tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, ascorbic acid, salicylic acid, or acetylsalicylic acid (aspirin), glycine, alanine, vanillin, iso Salts with
  • the arylethene derivatives of the present invention may exist in solvated forms, for example hydrated forms and unsolvated forms, and solvates of arylethene derivatives according to the present invention are suitable for all solvated forms having pharmaceutical activity. It is to include. That is, the arylethene derivative of the present invention is dissolved in a solvent that can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized or recrystallized after adding a free acid or free base to hydrate the hydrate. Including solvates may be formed. Accordingly, the novel compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization.
  • the arylethene derivatives of the present invention may have a chiral center and may exist as racemates, racemic mixtures and as individual enantiomers or diastereomers. Such isomers may be separated or resolved by conventional methods and any given isomer may be obtained by conventional synthesis or by stereospecific or asymmetric synthesis. All such isomeric forms and mixtures thereof are included within the scope of the present invention.
  • the arylethene derivatives of the present invention can be administered in the form of prodrugs that degrade in the human or animal body to provide the compounds of the present invention.
  • Prodrugs can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be induced to form the prodrug.
  • the pharmaceutical composition of the present invention is a non-toxic pharmaceutically acceptable carrier which is conventional in the arylethene derivative represented by Formula 1, prodrug thereof, solvate thereof, stereoisomer or pharmaceutically acceptable salt thereof, and Oral preparations or intravenous administrations such as tablets, pills, hard capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. It may be formulated as a parenteral preparation of sterile aqueous or oily solvents for subcutaneous, sublingual, intramuscular or intraocular administration.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are those commonly used in the preparation of lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and / or mineral oil, It is not limited to this.
  • Excipients that may be used in the pharmaceutical compositions of the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like.
  • the proportion and nature of the excipient can be determined by the solubility and chemical properties of the selected tablet, the chosen route of administration and standard pharmaceutical practice.
  • excipients include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, alginine acid, Sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the pharmaceutical composition of the present invention may be formulated in a parenteral dosage form, in which case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration or topical administration may be used, and a therapeutic agent for retinopathy In this regard, eye administration may be used, but is not limited thereto.
  • the pharmaceutical composition is an active ingredient, that is, an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable thereof. Salts are mixed in water with stabilizers or buffers to form solutions or suspensions, which solutions or suspensions may be prepared in unit dosage forms of ampoules or vials.
  • composition of the present invention may be sterile, or may further include adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and further include other therapeutically useful substances.
  • adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and further include other therapeutically useful substances.
  • the arylethene derivative represented by the formula (1), the prodrug, the solvate thereof, the stereoisomer or the pharmaceutically acceptable salt thereof represented by Formula 1, which is an active ingredient in the pharmaceutical composition according to the present invention may be used for mammals including humans. Dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Generally, the pharmaceutical composition may be included in the pharmaceutical composition in an effective amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 100 mg / kg body weight, and such pharmaceutical composition may be once or twice a day.
  • the biphasic can be administered via oral or parenteral routes. However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, which can specifically inhibit ERR ⁇ transcriptional activity, and a pharmaceutical It provides a pharmaceutical composition for the treatment of thyroid cancer, comprising a carrier which can be used as is, and used in combination with radioactive iodine.
  • the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a radioactive iodine which can specifically inhibit ERR ⁇ transcriptional activity. It provides a kit for treating thyroid cancer.
  • the arylethene derivative according to the present invention regulates MAP kinase (mitogen-activated protein kinase) by regulating the expression of endogenous ERR ⁇ protein, and improves the function of sodium iodide symporter (NIS) to improve membrane-localized NIS (membrane).
  • MAP kinase mitogen-activated protein kinase
  • NIS sodium iodide symporter
  • Increasing -localized NIS may improve radioactive iodine intake in the treatment of thyroid cancer.
  • Step 3 (E) -5- [4- (2,2- Dimethylpropanoyloxy ) Phenyl] -5- (4- Hydroxyphenyl ) -4-phenyl-phen-4-inoate ( A-3 Manufacturing
  • Zinc (8.8 g, 134 mmol) was added to tetrahydrofuran (130 mL), the temperature was lowered to 0 ° C., and titanium chloride (7.35 mL, 67 mmol) was added slowly. After heating the reaction solution at 60 ° C. for 2 hours, Compound A-2 (5 g, 16.8 mmol) and methyl 3-benzoylpropionate (4.8 g, 25.1 mmol) were added thereto. The reaction solution was heated at 50 ° C. for 1 hour. The reaction mixture was poured into 10% aqueous potassium carbonate solution, stirred for 30 minutes, and filtered using celite.
  • Step 4 (E)- tert -butyl 4- (2- (4- (5- methoxy -5- oxo -2-phenyl-1- (4- (pivaloyloxy) phenyl) pent-1-en-1-yl) phenoxy) ethyl) piperazine-1-carboxylate ( A-4 Manufacturing
  • Step 5 (Z) -4- (5-hydroxy-1- (4- (2- (4- ( tert - Butyloxycarbonyl ) piperazin -1-yl) ethoxy) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 6a Manufacturing
  • Step 3 (E) -methyl 5- (4- bromophenyl ) -5- (4- hydroxyphenyl )-4- phenylpent -4-enoate ( B-3 Manufacturing
  • Step 4 (E) -methyl 5- (4- (2- ( aziridin -One- yl ) ethoxy ) phenyl) -5- (4-bromophenyl) -4-phenylpent-4-enoate ( B-4 Manufacturing
  • Step 5 (E) -5- (4- (2- ( aziridin -One- yl ) ethoxy ) phenyl) -5- (4- bromophenyl ) -4-phenylpent-4-en-1-ol hydrochloride salt ( 13a Manufacturing
  • Step 1 methyl 5- (4- (pivaloyloxy) phenyl) pent-4-inoate ( C-1 Manufacturing
  • Step 2 (E)- tert -Butyl 3- (4- (5- Methoxy -5-oxo-2-phenyl-1- (4- ( Pivaloyloxy ) Phenyl) pent-1-en-1-yl) phenyl) azetidine-1-carboxylate ( C-2 Manufacturing
  • Step 3 tert -butyl (E) -3- (4- (5- hydroxy -1- (4- hydroxyphenyl ) -2-phenylpent-1-en-1-yl) phenyl) azetidine-1-carboxylate ( 18t Manufacturing
  • Step 1 methyl (E) -5- (4- bromophenyl ) -4-phenyl-5- (4- ( piperazin -1-yl) phenyl) pent-4-enoate ( D- 2 )of Produce
  • Step 2 (E) -5- (4- bromophenyl ) -4-phenyl-5- (4- ( piperazin -1-yl) phenyl) pent-4-en-1-ol ( 20a Manufacturing
  • Compounds 20b to 20l were prepared using the method of Example 40. Identification data of the prepared compounds 20a to 20l are shown in Table 4 below.
  • Step 1 methyl (E) -5- (4- (1- isopropylazetidin -3- yl ) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( E-2 Manufacturing
  • Step 2 (E) -4- (5- hydroxy -1- (4- (1- isopropylazetidin -3- yl ) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 22a Manufacturing
  • Compounds 22b to 22ae were prepared using the method of Example 52. Identification data of the prepared compounds 22a to 22ae are shown in Table 5 below.
  • Compounds 28b to 28g were prepared using the method of Example 95 above. Identification data of the prepared compounds 28a to 28g are shown in Table 8 below.
  • Step 1 methyl (E) -5- (4-((4- methylpiperazin -One- yl ) methyl) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( H-2 Manufacturing
  • Step 2 (E) -4- (5- hydroxy -1- (4-((4- methylpiperazin -One- yl ) methyl) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 30a Manufacturing
  • Compound 30b was prepared using the method of Example 102 above. Identification data of the prepared compounds 30a to 30b are shown in Table 9 below.
  • Step 1 methyl (Z) -5- ( indolin -5- yl ) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( I- 2 )of Produce
  • Step 2 methyl (Z) -4-phenyl-5- (4- ( pivaloyloxy ) phenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) indolin-5-yl) pent-4-enoate ( I-3 Manufacturing
  • Step 3 (Z) -4- (5- hydroxy -2-phenyl-1- (1- (2- ( pyrrolidin -1-yl) ethyl) indolin-5-yl) pent-1-en-1-yl) phenol ( 33 Manufacturing
  • Step 1 methyl (Z) -5- (1H- indol -5- yl ) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( J-2 Manufacturing
  • Step 2 methyl (Z) -4-phenyl-5- (1- (2- ( piperidin -One- yl ) ethyl) -1H- indol -5-yl) -5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( J-3 Manufacturing
  • Step 3 (Z) -4- (5- hydroxy -2-phenyl-1- (1- (2- ( piperidin -One- yl ) ethyl) -1H-indol-5-yl) pent-1-en-1-yl) phenol ( 36 Manufacturing
  • Step 1 methyl (E) -5- (4- (2- (3- azabicyclo [3.1.0] hexan -3-yl) ethoxy) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( K- 2 )of Produce
  • Step 2 (Z) -4- (1- (4- (2- (3- azabicyclo [3.1.0] hexan -3- yl ) ethoxy ) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol ( 38a Manufacturing
  • Step 1 methyl (Z) -5- (4- ( dimethyl ( (4- methylpiperazin -1-yl) methyl) silyl) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( L- 2 )of Produce
  • Step 2 (Z) -4- (1- (4- ( dimethyl ( (4- methylpiperazin -1-yl) methyl) silyl) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol ( 42a Manufacturing
  • Step 1 methyl (E) -4-phenyl-5- (4- (2- ( piperidin -One- yl ) acetamido ) phenyl) -5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( M-2 Manufacturing
  • Step 2 (E) -N- (4- (5- hydroxy -1- (4- hydroxyphenyl )-2- phenylpent -1-en-1-yl) phenyl) -2- (piperidin-1-yl) acetamide ( 44 Manufacturing
  • Step 1 tert -butyl (3aR, 6aS) -5- (2-((4-((E) -5-methoxy-5-oxo-2-phenyl-1- (4- (pivaloyloxy) phenyl) pent-1-en- 1-yl) phenyl) amino) -2-oxoethyl) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate ( N-1 Manufacturing
  • Step 2 tert -butyl (3aR, 6aS) -5- (2-((4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) amino) -2-oxoethyl) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate ( N-2 Manufacturing
  • Step 3 2-((3aR, 6aS) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl) -N- (4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) acetamide ( 46 Manufacturing
  • Step 1 (Z) -5- (4- aminophenyl ) -5- (4- (4- isopropylpiperazin -One- yl ) phenyl) -4-phenylpent-4-en-1-ol ( O- One )of Produce
  • Step 2 (Z) -1- (4- (5- hydroxy -1- (4- (4- isopropylpiperazin -One- yl ) phenyl) -2-phenylpent-1-en-1-yl) phenyl) guanidine ( 50 )of Produce
  • Step 1 tert -butyl ((E)-((tert-butoxycarbonyl) imino) (4- (4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) piperazin-1-yl) methyl) carbamate ( P-1 Manufacturing
  • Step 2 (E) -4- (4- (5- hydroxy -1- (4- hydroxyphenyl )-2- phenylpent -1-en-1-yl) phenyl) piperazine-1-carboximidamide ( 52 Manufacturing
  • the arylethene derivative of the present invention was sequentially added to a 384 well plate so that the concentration was diluted by 2 times, starting with a final concentration of 10 ⁇ M.
  • the GST-coupled ERR gamma LBD ligand-binding domain
  • the fluorescien-conjugated coacitivators PGC1a and Tb-a-GST antibodies were added to 500 nM and 5 nM, respectively.
  • the reaction was gently shaken at 20 ° C. for 1 hour.
  • binding activity was measured by TR-FRET method. That is, after excitation at 340nm, the emission value was measured at 495nm and 520nm, respectively, the result analysis was 490nm measurement value / 520nm measurement value, and the analysis program used Prism 6.
  • ERR alpha binding assay used ERR alpha LBD combined with GST. All other methods were the same as the ERR gamma binding assay.
  • ERR beta binding assay GST-coupled ERR alpha LBD was used at a final concentration of 10 nM and the fluorescien-conjugated coacitivator PGC1a was 250 nM. All other experimental methods were the same as the ERR gamma binding assay.
  • ER alpha binding assay GST-coupled ER alpha LBD (ligand-binding domain) was added to a 384 well plate to which the arylethene derivative of the present invention was added to a final concentration of 7.3 nM.
  • fluorescien-conjugated coacitivator PGC1a and Tb-a-GST antibodies were added to 250nM, 5nM, and agonist beta-estradiol to a final concentration of 4nM. All subsequent experiments were identical to the ERR gamma binding assay.
  • AD293 was incubated in a 24 well plate for 24 hours using DMEM High glucose (Hyclone, USA) culture with 0.5% FBS at 9 ⁇ 10 4 / well. Replace with DMEM High glucose culture medium with 10% FBS, mix with Trans IT-LT1 transfection reagent (Mirus, USA), pCMX-Gal4-ERR ⁇ , pFR-luciferase reporter plasmid, and pCMV- ⁇ -gal. Time incubation. Then, luciferase activity assay and ⁇ -gal assay were performed with lysate obtained after 24 hours of arylethene derivative of the present invention. All results were derived from three or more independent and repeated experiments.
  • Cpds refers to inverse agonist functional activity when the compound is treated
  • Ref 5182 refers to the activity of the reference compound GSK5182 for data validation every time the assay is performed.
  • Cpds / Ref 5182 refers to the degree of activity of the arylethene derivative of the present invention relative to the reference compound.
  • CYP450 cytochrome P450
  • Human liver microsomes (0.25 mg / ml) and 0.1M phosphate buffer (pH 7.4), substrate drug cocktails of 5 drug metabolic enzymes (Phenacetin 50 ⁇ M, Diclofenac 10 ⁇ M, S-mephenytoin 100 ⁇ M, Dextromethorphan 5 ⁇ M, Midazolam 2.5 ⁇ M) and arylethene derivatives of the present invention were added at concentrations of 0 and 10 ⁇ M, respectively, and pre-incubated at 37 ° C. for 5 minutes, followed by the addition of a NADPH generation system solution and incubation at 37 ° C. for 15 minutes.
  • 5 drug metabolic enzymes Phenacetin 50 ⁇ M, Diclofenac 10 ⁇ M, S-mephenytoin 100 ⁇ M, Dextromethorphan 5 ⁇ M, Midazolam 2.5 ⁇ M
  • arylethene derivatives of the present invention were added at concentrations of 0 and 10 ⁇ M, respectively, and pre-incuba
  • liver microsomes Human, Dog, Rat, Mouse 0.5 mg / ml
  • 0.1 M phosphate buffer (pH 7.4) and arylethene derivatives of the present invention were added at a concentration of 1 ⁇ M and pre-incubated at 37 ° C. for 5 minutes. After that, the NADPH Regeneration system solution was added and incubated at 37 ° C. for 30 minutes. Then, to terminate the reaction, acetonitrile solution containing chlorpropamide was added, centrifuged for 5 minutes (14,000 rpm, 4 ° C.), and the supernatant was injected into the LC-MS / MS system. By analyzing, the metabolic stability of the arylethene derivative of the present invention was evaluated.
  • PAMPA was developed to test cell membrane permeability of a substance in vitro, and was performed using lipid tri-layer PVDF membrane of cornig gentest (NY, US). All reagents used were Sigma (MO, US). Purchased from First, dilute the test substance to a final concentration of 10 mM in PBS (pH7.4), add 300 mL to the bottom well of a 96 transwell equipped with PVDF membrane, and add 200 mL of PBS to the upper well. . After the plate is reacted at 25 ° C. for 5 hours, transfer 20 mL of solution from each well to a new container, and add 80 mL of acetonitrile containing 4 mM chloropropamide. The concentration of material in solution is analyzed using LC-MS / MS (ThermoFisher Scientific, MO, US), and the permeability of the material is calculated according to the formula reported in the reference.
  • E-4031 Effective IC50: 10-90nM
  • membrane prepared with hERG channel and fluorescent tracer As a positive control, E-4031 (Effective IC50: 10-90nM) compound was diluted in 3-fold stepwise, mixed with membrane prepared with hERG channel and fluorescent tracer and reacted for 4 hours. measured to obtain the IC 50.
  • Fluorescence Intensity (Excitation at 530nm, Emission at 590nm) at 16 point concentrations diluted in stages was measured and compared with DMSO solvent control.
  • hERG Fluorescence Polarization Assay (Invitrogen: PV5365) kit was used.
  • the drug is injected into the tail vein at a dose of 1 mg / kg (syringe).
  • Oral administration (PO) to the drug orally (10 mg / kg) oral zondec).
  • CAL-62 an undifferentiated thyroid cancer cell line, was purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen. Cell lines were all maintained at 37 ° C. under 5% CO 2 atmosphere in DMEM medium, highly supplemented with 10% FBS, 1% antibiotic-antifungal (Hyclone). Retroviruses expressing the enhanced firefly luciferase gene (effluc) were treated with CAL-62 cells to establish a cell line stably expressing the effluc gene. This established cell line was named CAL-62 / effluc cells.
  • HBSS Hank 'balanced salt solution
  • KClO 4 as a specific inhibitor for NIS
  • each target gene is as follows; ERR ⁇ (forward, 5'- CAG ACG CCA GTG GGA GCT A -3 '; reverse, 5'- TGG CGA GTC AAG TCC GTT CT-3'), NIS (forward, 5'- TCT AAC CGA TGC TCA CCT CTT CTG -3 '; reverse, 5'- AGA TGA TGG CAC CTC CTT GAA CC -3'), and acidic ribosomal protein 36B4 (forward, 5'-CCA CGC TGC TGA ACA TGC T -3 '; reverse, 5'- TCG AAC ACC TGC TGG ATG AC -3 '). Each target gene was normalized using 36B4 gene.
  • Cells were plated in 6-well plates and left for 24 hours. After 24 hours of treatment with 12 ⁇ M compound 18a, the drug-containing medium was discarded and the cells washed twice with PBS. The medium was then replaced with DMEM in the presence or absence of 50 ⁇ Ci 131 I (KIRAMS, Korea) for 6 hours. Cells were washed with cold bHBSS and placed in normal culture medium for a time corresponding to six doublings. Finally, cells were fixed in 4% paraformaldehyde (PFA) solution and stained with 0.05% crystal violet. Control colonies and 131 I treated colonies with more than 50 cells were counted.
  • PFA paraformaldehyde
  • Cells were treated for 24 hours without or with compound 18a, washed twice with cold PBS and lysed with RIPA buffer (Roche) containing a complete protease inhibitor cocktail.
  • RIPA buffer containing a complete protease inhibitor cocktail.
  • samples were prepared using a protein biotinylation kit (EZ-Link TM Sulfo-NHS-Biotin, Thermo Scientific) according to manufacturer's instructions.
  • the cells were then washed twice quickly with PBS / CM before lysis using RIPA buffer (Roche) containing a protease inhibitor cocktail and a phosphatase inhibitor with constant shaking at 4 ° C. for 1 hour.
  • the lysate was centrifuged at 16,000 g for 30 minutes at 4 ° C. Part of the supernatant was used for total cell protein immunoblot. The remaining sample was used to obtain membrane protein by incubating with 100 ⁇ L Streptavidin beads (Thermo Scientific) for 1 hour at room temperature.
  • the beads were washed three times with RIPA buffer and the bound protein was washed with 50 ⁇ L of Laemmli buffer (62.5 M Tris, pH 6.8; 20% glycerol; 2% SDS; 5% b- for 30 minutes at room temperature). Mercaptoethanol; and 0.01% brominephenol blue). Equal amounts of total cell membrane protein and biotinylated cell membrane protein were loaded on each lane and resolved by 4-12% gradient Bis-Tris gel (Invitrogen). Protein was transferred to 0.2 ⁇ m PVDF membrane (Invitrogen).
  • Membranes are incubated with primary murine monoclonal human NIS-specific antibody (dilution 1: 1000, Thermo Scientific, Catalog #: MS-1653-P1, clone: FP5A), followed by room temperature with HRP-conjugated secondary antibody Incubated at. ECL-Plus (Amersham Pharmacia) was used to detect peroxidase activity according to the manufacturer's method. Similarly, for other proteins, an equivalent amount of protein was loaded in each lane and digested by 4-12% gradient Bis-Tris gel (Invitrogen). Protein was transferred to 0.2 ⁇ m PVDF membrane (Invitrogen).
  • Membranes were incubated with primary antibodies (ERR ⁇ , pERK1 / 2, ⁇ -actin) overnight at 4 ° C. and then incubated with appropriate HRP-conjugated secondary antibodies at room temperature. Peroxidase activity was detected using ECL-Plus according to the manufacturer's protocol. Band density was determined using ImageJ software.
  • Nude mice (Balb / c nu / nu, female, 6 weeks old) were used and all animals were bred normally in the animal laboratory at Chilgok Kyungpook National University Hospital DMRC Center. Tumor formation was performed by subcutaneous injection of 5 ⁇ 10 6 CAL-62 / effluc cells into the left thigh of nude mice. Tumors were extracted, sliced into small size (20 mg or more), and injected again into nude mice for tumor formation.
  • the CAL-62 / effluc mouse tumor model was divided into the following groups; Group 1: vehicle, group 2: 100 mpk compound 18a, group 3: 200 mpk compound 18a. Mice in each group were orally administered vehicle (100% PEG) and compound 18a (100 mpk, 200 mpk) daily for 6 days. Bioluminescent imaging was performed to observe tumor growth differences before and after administration. Mouse weight changes were observed every other day during drug administration.
  • mice were administered 125 I (5 uCi / mouse) intravenously.
  • 125 I 5 uCi / mouse
  • Each organ was then transferred to a 5 ml test tube and then radioactivity was measured using a gamma counter.
  • the intake of 125 I in organs was expressed as percentage injected dose per gram (% ID / g).
  • mice were intraperitoneally injected with D-luciferin (3 mg / mouse). About 10 minutes after injection, mice were inhaled with anesthesia (1-2% isoflurane gas) and placed on an IVIS Lumina III (PerkinElmer) imaging bed. The image acquisition time was automatically set, and then the optical image was acquired. Optical imaging signals from tumors were quantified using Living imaging software (version 2.12, PerkinElmer).
  • Compound 18a induced a sharp increase in cell membrane-localized NIS protein with mature and immature morphology in ATC cells compared to control cells (FIG. 14). Quantitative analysis of band intensities showed 8.1- and 6.4-fold increases in membrane fully glycosylated and partially glycosylated NIS proteins, respectively, in CAL62 cells (FIG. 15).
  • the CAL62-effluc mouse tumor model was established and grouped as follows (FIG. 18, Group 1: Vehicle, Group 2: 100 mpk Compound 18a, Group 3: 200 mpk Compound 18a). Mice in each group were daily orally administered vehicle (100% PEG), compound 18a (100 mpk, 200 mpk) for 6 days. Bioluminescent imaging was performed to monitor tumor growth differences before and after administration. Radioisotope (I-125) was administered to the mice the next day after the last dose of the drug, and after 2 hours, the mice were sacrificed and all organs were removed and the radiation levels were measured by gamma counter. Treatment with Compound 18a confirmed a concentration-dependent increase in radioactive iodine intake in CAL62 tumors (FIG. 19).
  • the 100mpk, 200mpk compound 18a group showed an increase of 4.4 times and 16.2 times radioiodine intake.
  • the compound 18a showed a marked tumor growth inhibitory effect (FIG. 20).
  • Drug concentration-dependent tumor growth inhibition effect was shown (Fig. 21).
  • the rapid weight change of mice was not seen in all groups (FIG. 22).
  • the arylethene derivative of the present invention is a novel compound, which shows very high inhibitory activity against ERR ⁇ as well as improved drug stability, pharmacological activity and toxicity compared to the existing GSK5182 compound, and thus mediated by ERR ⁇ .
  • ERR ⁇ enzyme-mediated retinopathy
  • the arylethene derivatives of the present invention can specifically inhibit ERR ⁇ transcriptional activity significantly remarkably compared to GSK5182, and as a result, can increase radioisotope uptake from the cellular level to the animal level. Therefore, it is possible to significantly increase the therapeutic effect of radioactive iodine therapy for the treatment of cancer, and to effectively manufacture cancer cells with enhanced sodium iodide symporter (NIS) function when administered to cancer cells, and to apply them to related studies and clinical applications for the treatment of undifferentiated thyroid cancer. There is an excellent effect that can be made easier.
  • NIS sodium iodide symporter

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Abstract

The present invention relates to an aryl ethane derivative, for inhibiting an estrogen-related receptor gamma (ERRγ) activity, a prodrug of same, a solvate of same, a stereoisomer of same or pharmaceutically acceptable salts of same, and a pharmaceutical composition containing same as an active ingredient.

Description

신규한 아릴에텐 유도체 및 이를 유효성분으로 함유하는 약제학적 조성물Novel aryethene derivatives and pharmaceutical compositions containing them as active ingredients
본 발명은 에스트로겐 관련 수용체 감마(Estrogen related receptor gamma, 이하 ‘ERRγ’이라 함)의 활성을 억제하는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염 및 이를 유효성분으로 함유하는 약제학적 조성물에 관한 것이다.The present invention relates to arylethene derivatives that inhibit the activity of Estrogen related receptor gamma (hereinafter referred to as 'ERRγ'), prodrugs thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof; and It relates to a pharmaceutical composition containing this as an active ingredient.
세포 내 유전자발현 변화를 통해 세포의 발생이나 성장, 분화를 조절하기 위해서는 호르몬에 반응하는 호르몬 수용체가 필요한데 크게 세포막 수용체와 핵 수용체가 있다. 그 중에서 핵 수용체로 그 중 결합하는 리간드가 밝혀지지 않은 고아 핵 수용체(Orphan Nuclear Receptor)에 대한 관심이 증대되고 있다.In order to regulate the generation, growth, and differentiation of cells through changes in gene expression, hormone receptors that respond to hormones are required. There are largely cell membrane receptors and nuclear receptors. Among them, there is a growing interest in orphan nuclear receptors (Orphan Nuclear Receptor), the ligand that binds to the nuclear receptor is not known.
고아 핵 수용체 중의 하나인 ERR(Eestrogen Related Receptor)에는 ERRα, ERRβ 및 ERRγ의 3가지 타입이 존재하며, 각각 활성화되는 위치가 상이하다. There are three types of ERRα, ERRβ, and ERRγ in the orphan nuclear receptor, ERR (Eestrogen Related Receptor), and the activated positions are different.
특히 ERRγ는 척수와 중추신경계에서 활성을 보이며, 간에서의 포도당 생합성에 관여하는 전사조절 단백질로, 리간드와 결합하면 스스로 전사활성이 증가되어 포도당 합성관련 유전자가 발현되도록 돕는 핵 호르몬 수용체이다. 즉, ERRγ는 포도당대사에 직접적으로 관여한다.In particular, ERRγ is a transcriptional regulatory protein that is active in the spinal cord and central nervous system, and is involved in glucose biosynthesis in the liver. It is a nuclear hormone receptor that helps to express glucose synthesis-related genes by binding to ligands. In other words, ERRγ is directly involved in glucose metabolism.
또한, ERRγ는 NR3B3로 불리는 인간 핵 수용체 단백질로서, ESRRG 유전자에 의해 인코딩된다. ERRγ는 전사에 있어서 지속적 활성제(constitutive activator)로서 기능한다. ERRγ는 스테로이드 호르몬 수용체의 핵 호르몬 수용체 패밀리의 일 구성원이다.In addition, ERRγ is a human nuclear receptor protein called NR3B3, which is encoded by the ESRRG gene. ERRγ functions as a constitutive activator in transcription. ERRγ is a member of the nuclear hormone receptor family of steroid hormone receptors.
ERRγ 단백질은 심근에서 지방산 산화 및 미토콘드리아 바이오제네시스(biogenesis)에 연관된 다양한 유전자의 주요 조절자로 알려진 바 있으며, 간에서 포도당 생성에 관여하는 것으로도 알려져 있다.The ERRγ protein has been known as a major regulator of various genes involved in fatty acid oxidation and mitochondrial biogeneration in the myocardium, and is also known to be involved in glucose production in the liver.
한편, 당뇨망막병증은, 당뇨가 있는 환자에서 특유의 망막의 순환장애가 발생하여 발병하는 질환으로, 당뇨병성 신경병증, 당뇨병성 신증과 함께 당뇨병에서 3대 미세혈관합병증 중 하나이다. 당뇨망막병증의 발생은 당뇨병을 앓은 유병기간과 연관이 있는데 제1형에 해당하는 30세 이전에 진단된 당뇨병의 경우 유병기간이 5년 이하일 때 17%, 15년 이상일 때 98%에서 당뇨망막병증이 발생하고, 이 중 더 악화된 증식당뇨망막병증은 10년 이하일 때는 약 1%, 35년 이상에서는 67%에서 발생한다. 제2형 당뇨병에서는 유병기간 5년 이하에서는 29%, 15년 이상에서는 78%이며, 증식당뇨망막병증은 5년 이하에서는 2%, 15년 이상에서는 16%에서 발생한다고 알려져 있다. 당뇨병 환자의 망막에서는 망막모세혈관 기저막의 비후, 혈관주위 세포의 소실, 미세혈관류의 발생 등 모세혈관에서 혈관의 변화가 나타나며, 시간이 경과함에 따라 광범위한 모세혈관 비관류에 이어 망막신생혈관 역시 발생할 수 있는 것으로 알려져 있다. 이러한 당뇨망막병증은 당뇨 합병증의 일종이기는 하나, 일단 발병하게 되면 혈당 조절 등으로 그 진행을 막기 어려우며, 망막병증에 특이적인 치료 방법이 요구된다.On the other hand, diabetic retinopathy is a disease caused by a specific retinal circulation disorder in diabetic patients and is one of three major microvascular complications in diabetes along with diabetic neuropathy and diabetic nephropathy. The incidence of diabetic retinopathy has been linked to the prevalence of diabetes mellitus. For diabetics diagnosed before age 30, type 1, 17% when the disease is under 5 years and 98% when the disease is 15 years or more. Among these, worsening proliferative diabetic retinopathy occurs in about 1% of patients under 10 years of age and 67% of patients over 35 years of age. In type 2 diabetes, 29% of patients are younger than 5 years, 78% of patients are older than 15 years, and proliferative diabetic retinopathy is reported in 2% of patients younger than 5 years and 16% of patients over 15 years. In diabetic retina, changes in blood vessels in capillaries such as thickening of retinal capillary basement membrane, loss of perivascular cells, and microvascular perfusion occur. Over time, retinal neovascularization also occurs after extensive capillary nonperfusion. It is known that it can. Although diabetic retinopathy is a type of diabetic complication, once developed, it is difficult to prevent its progression due to blood sugar control, and a specific treatment method for retinopathy is required.
최근의 연구는 (Z)-4-(1-(4-(2-(디메틸아미노)에톡시)페닐)-5-히드록시-2-페닐펜트-1-엔-1-일)페놀인 GSK5182로 알려진 저분자 유기 화합물이 ERRγ에 리간드로 작용하여 ERRγ의 활성을 저해함으로써 고혈당과 인슐린 저항성을 완화하는 등의 항당뇨 효과 및 망막병증의 치료 효과를 보이는 것으로 보고하였다.A recent study was GSK5182 which is (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol It has been reported that a small molecule organic compound known as a ligand acts as a ligand to ERRγ and inhibits the activity of ERRγ, thereby exhibiting antidiabetic effects such as relieving hyperglycemia and insulin resistance and treating retinopathy.
Figure PCTKR2016010369-appb-I000001
Figure PCTKR2016010369-appb-I000001
종래 보고된 GSK5182에 비해 ERRγ의 전사활성을 특이적으로 현저하게 억제하는 새로운 물질의 개발이 요구되고 있다.There is a demand for the development of a new substance that specifically inhibits the transcriptional activity of ERRγ significantly as compared to the conventionally reported GSK5182.
한편, 미분화 갑상선암(anaplastic thyroid cancer; ATC)은 인간에게 발병하는 것으로 알려진 가장 공격적이고 치명적인 암들 중 하나이다. ATC는 갑상선샘으로부터 폐, 뼈, 국소 임파절, 및 뇌로 급속히 전이된다. 이는 대부분의 갑상선암을 설명하는 고분화(well-differentiated) 양성 갑상선암의 성질과 대조되며, 따라서, 수술, 방사선 요법, 및 화학 요법을 단독으로 또는 조합한 ATC의 치료는 환자 생존에 효과를 나타내지 못해왔다. 그 결과, 신규한 치료 방법의 개발이 절실히 요구된다.Anaplastic thyroid cancer (ATC), on the other hand, is one of the most aggressive and deadly cancers known to occur in humans. ATC rapidly metastasizes from the thyroid gland to the lungs, bones, regional lymph nodes, and brain. This contrasts with the nature of well-differentiated benign thyroid cancers, which account for most thyroid cancers, and therefore, treatment of ATC alone or in combination with surgery, radiation therapy, and chemotherapy has not been effective in patient survival. . As a result, the development of new treatment methods is urgently needed.
나트륨 요오드 공수송체(sodium iodide symporter; NIS)는 요오드의 세포 내 활성 유입을 매개하는 세포막(plasma membrane) 당단백질이다. 갑상선암에서, 내생의 NIS는 임상적 상황에서 방사성 요오드 요법의 광범위한 적용을 수용하며, 이는 수년에 걸쳐 최소의 부작용으로 악성 세포들을 제거하는 효과적인 치료법으로 알려져 왔다. ATC 세포를 포함하여, 저분화성 암세포는 NIS 수준의 감소를 이끄는 점진적인 탈분화를 나타내는 경향이 있다. 이는 ATC 세포가 높은 농도로 요오드를 세포 내에 축적하지 못하게 하고, 이에 따라 방사성 요오드 요법에 세포 내성을 초래하여, 결국 불량한 예후로 이끈다. 따라서, 유전자 전달 및 후성유전자(epigenome)-변경 약물 등을 이용한 후성유전학적 조절과 같은 몇 가지 방법을 이용하여 ATC 세포에서 NIS 기능을 회복시키기 위한 많은 시도가 수행되어 왔지만, 이제까지 만족스러운 결과는 얻어지지 않았다. Sodium iodide symporter (NIS) is a plasma membrane glycoprotein that mediates the active influx of iodine into cells. In thyroid cancer, endogenous NIS accommodates the widespread application of radioactive iodine therapy in clinical situations, which has been known as an effective treatment for removing malignant cells with minimal side effects over the years. Low differentiated cancer cells, including ATC cells, tend to exhibit progressive dedifferentiation leading to a decrease in NIS levels. This prevents ATC cells from accumulating iodine in the cells at high concentrations, thereby causing cellular resistance to radioactive iodine therapy, which in turn leads to poor prognosis. Thus, many attempts have been made to restore NIS function in ATC cells using several methods, such as gene transfer and epigenetic regulation with epigenome-modifying drugs, but until now satisfactory results have been obtained. I didn't lose.
ERRγ의 생물학적 효과는 각종 질병 모델 (2형 진성 당뇨병, 알코올-유도된 산화적 스트레스, 간 손상 및 손상된 간의 당신생작용(gluconeogenesis)을 통한 미생물 감염, 간 인슐린 시그널링 및 철 대사와 같은 몇몇 대사성 질환)에서 광범위하게 연구되어 왔으나, ATC에서 NIS 기능에 대한 ERRγ의 역할은 지금까지 명확히 연구되어 있지 않다. 최근의 연구는(Z)-4-(1-(4-(2-(디메틸아미노)에톡시)페닐)-5-히드록시-2-페닐펜트-1-엔-1-일)페놀인 GSK5182로 알려진 저분자 유기 화합물이 ERRγ에 리간드로 작용하여 ERRγ 활성을 저해함으로써 NIS의 기능을 향상시켜 ATC 세포내 방사성요오드 섭취를 증가시키고 최종적으로는 방사성옥소치료 증대 효과를 보이는 것으로 보고하였다. 하지만, ATC 마우스 종양모델에 GSK5182를 투여했을 때에는 종양 내 방사성요오드 섭취 증가가 안되었다. 따라서 GSK5182에 비해 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있으며 그 결과 세포수준에서부터 동물수준에서까지 방사성동위원소 섭취 증가를 유발할 수 있는 새로운 물질 개발이 요구되고 있다.Biological effects of ERRγ have been linked to various disease models (some metabolic diseases such as type 2 diabetes mellitus, alcohol-induced oxidative stress, liver damage and microbial infection through damaged gluconeogenesis, liver insulin signaling, and iron metabolism). Has been studied extensively, but the role of ERRγ on NIS function in ATC has not been clearly studied to date. A recent study was GSK5182 which is (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol It has been reported that a small molecule organic compound known as a ligand acts as a ligand to ERRγ, thereby inhibiting ERRγ activity, thereby improving NIS function, increasing radioactive iodine intake in ATC cells, and finally increasing radioiodine treatment. However, administration of GSK5182 to the ATC mouse tumor model did not result in increased tumor iodine uptake. Therefore, compared with GSK5182, it is possible to specifically inhibit ERRγ transcriptional activity, and as a result, it is required to develop a new substance that can cause an increase in radioisotope intake from the cellular level to the animal level.
이에, 본 발명의 발명자들은 아릴에텐 유도체에 특정 치환체의 도입으로 인하여 종래 보고된 GSK5182과 비교해 ERRγ의 저해 활성이 더욱 우수해짐과 동시에 약물 안정성, 약리 활성 및 독성이 개선됨을 발견하고 본 발명을 완성하였다.Accordingly, the inventors of the present invention found that the introduction of specific substituents on the arylethene derivatives resulted in more excellent inhibitory activity of ERRγ and improved drug stability, pharmacological activity and toxicity compared to the conventionally reported GSK5182. It was.
본 발명의 목적은 ERRγ의 활성을 효과적으로 억제할 수 있는 신규한 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 제공하는 것이다.It is an object of the present invention to provide novel arylethene derivatives, prodrugs thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof that can effectively inhibit the activity of ERRγ.
본 발명의 다른 목적은 상기 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 ERRγ에 의해 매개되는 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is a pharmaceutical for the prophylaxis or treatment of a disease mediated by ERRγ containing the arylethene derivative, its prodrug, solvate, stereoisomer or pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a composition.
본 발명의 또 다른 목적은 상기 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 망막병증의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating retinopathy, containing the arylethene derivative, prodrug thereof, solvate thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof as an active ingredient. It is.
본 발명의 또 다른 목적은 상기 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 약제학적으로 하용 가능한 담체를 포함하고, 방사성 요오드와 병용하여 사용되는 갑상선암 치료용 약제학적 조성물을 제공하는 것이다.Still another object of the present invention includes the above arylethene derivatives, their prodrugs, their solvates, their stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and used in combination with radioactive iodine It is to provide a pharmaceutical composition for treating thyroid cancer.
본 발명의 또 다른 목적은 상기 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 방사성 요오드를 포함하는 갑상선암 치료용 키트를 제공하는 것이다.Still another object of the present invention is to provide a kit for treating thyroid cancer comprising the arylethene derivative, its prodrug, its solvate, its stereoisomer or pharmaceutically acceptable salt thereof, and radioactive iodine.
상기 목적을 달성하기 위하여, 본 발명은 ERRγ의 활성을 효과적으로 억제할 수 있는 신규한 화합물로서, 하기 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 제공한다:In order to achieve the above object, the present invention is a novel compound that can effectively inhibit the activity of ERRγ, an arylethene derivative represented by the following formula (1), prodrug thereof, solvate thereof, stereoisomer or pharmaceutical Provide acceptable salts thereof:
[화학식 1][Formula 1]
Figure PCTKR2016010369-appb-I000002
Figure PCTKR2016010369-appb-I000002
상기 화학식 1에서, In Chemical Formula 1,
L은 (C6-C20)아릴렌, (C3-C20)헤테로아릴렌 또는 (C3-C20)융합헤테로고리이고;L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
R1은 (C3-C20)헤테로사이클로알킬, (C3-C20)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
R11 내지 R15는 각각 독립적으로 (C3-C20)헤테로사이클로알킬이고; R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl;
R16 및 R17는 각각 독립적으로 (C1-C20)알킬이고;R 16 and R 17 are each independently (C 1 -C 20) alkyl;
m은 1 내지 3의 정수이고;m is an integer from 1 to 3;
n은 0 또는 1의 정수이고;n is an integer of 0 or 1;
Ar은 (C6-C20)아릴 또는 (C3-C20)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C20)알킬, 할로(C1-C20)알킬, (C1-C20)알콕시, 니트로, 시아노, -NR21R22, (C1-C20)알킬카보닐옥시, (C1-C20)알킬카보닐아미노, 구아니디노, -SO2-R23 및 -OSO2-R24으로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
R21 및 R22는 각각 독립적으로 수소, (C1-C20)알킬설포닐 또는 (C3-C20)시클로알킬설포닐이고;R 21 and R 22 are each independently hydrogen, (C1-C20) alkylsulfonyl or (C3-C20) cycloalkylsulfonyl;
R23 및 R24는 각각 독립적으로 (C1-C20)알킬, 할로(C1-C20)알킬 또는 (C3-C20)시클로알킬이고;R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
R2는 히드록시, 할로겐, (C1-C20)알킬카보닐옥시 또는 (C1-C20)알킬설포닐옥시이고;R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C20)알킬, (C3-C20)사이클로알킬, (C2-C20)알케닐, 아미디노(amidino), (C1-C20)알콕시카보닐, 히드록시, 히드록시(C1-C20)알킬 및 디(C1-C20)알킬아미노(C1-C20)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
상기 헤테로사이클로알킬 및 헤테로아릴은 N, O 및 S로부터 선택되는 하나 이상의 헤테로 원자를 포함하며, 상기 헤테로사이클로알킬은 고리 내 탄소 원자 또는 질소 원자를 결합 부위로 갖는 포화 또는 불포화된 모노, 바이 또는 스피로 고리이다.The heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
또한, 본 발명은 상기 화학식 1로 표시되는 아릴에텐 유도체에 대한 우수한 ERRγ 억제 활성을 확인함으로써, 상기 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 ERRγ에 의해 매개되는 질환의 예방 또는 치료용 약제학적 조성물을 제공한다. In addition, the present invention by confirming the excellent ERRγ inhibitory activity against the aryl ethene derivative represented by the formula (1), the aryl ethene derivative, its prodrug, solvate, stereoisomer or pharmaceutically acceptable salt thereof It provides a pharmaceutical composition for the prevention or treatment of diseases mediated by ERRγ containing as an active ingredient.
또한, 본 발명은 ERRγ의 활성을 효과적으로 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 망막병증의 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention is a retinopathy containing an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient capable of effectively inhibiting the activity of ERRγ. It provides a pharmaceutical composition for the prophylaxis or treatment of.
또한, 본 발명은 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 약제학적으로 하용 가능한 담체를 포함하고, 방사성 요오드와 병용하여 사용되는 갑상선암 치료용 약제학적 조성물을 제공한다.In addition, the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, which can specifically inhibit ERRγ transcriptional activity, and a pharmaceutical It provides a pharmaceutical composition for the treatment of thyroid cancer, comprising a carrier which can be used as is, and used in combination with radioactive iodine.
또한, 본 발명은 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 방사성 요오드를 포함하는 갑상선암 치료용 키트를 제공한다.In addition, the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a radioactive iodine which can specifically inhibit ERRγ transcriptional activity. It provides a kit for treating thyroid cancer.
본 발명의 아릴에텐 유도체는 신규한 화합물로서, 기존의 GSK5182 화합물과 비교하여 ERRγ에 대한 매우 높은 억제 활성을 나타냄과 동시에 약물 안정성, 약리 활성 및 독성이 개선된 효과를 나타내므로, ERRγ에 의해 매개되는 질환, 특히 비만, 당뇨, 고지혈증, 지방간 또는 동맥경화 등과 같은 대사성 질환 뿐만 아니라 망막병증에 대한 효율적인 예방 및 치료제로 부작용없이 유용하게 사용할 수 있다.The arylethene derivative of the present invention is a novel compound, which shows very high inhibitory activity against ERRγ as well as improved drug stability, pharmacological activity and toxicity compared to the existing GSK5182 compound, and thus mediated by ERRγ. As an effective prophylactic and therapeutic agent for retinopathy as well as metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver or arteriosclerosis, etc., it can be usefully used without side effects.
또한, 본 발명의 아릴에텐 유도체는 GSK5182에 비해 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있으며 그 결과 세포수준에서부터 동물수준에서까지 방사성동위원소 섭취 증가를 유발할 수 있다. 따라서, 암의 치료를 위한 방사성 요오드 요법의 치료 효과를 현저히 증가시킬 수 있으며, 암세포에 투여시 NIS(sodium iodide symporter) 기능이 향상된 암세포를 효과적으로 제조함으로써 미분화 갑상선암 치료를 위한 관련 연구 및 임상에의 적용을 보다 용이하게 할 수 있는 우수한 효과가 있다.In addition, the arylethene derivatives of the present invention can specifically inhibit ERRγ transcriptional activity significantly remarkably compared to GSK5182, and as a result, can increase radioisotope uptake from the cellular level to the animal level. Therefore, it is possible to significantly increase the therapeutic effect of radioactive iodine therapy for the treatment of cancer, and to effectively manufacture cancer cells with enhanced sodium iodide symporter (NIS) function when administered to cancer cells, and to apply them to related studies and clinical applications for the treatment of undifferentiated thyroid cancer. There is an excellent effect that can be made easier.
도 1 내지 도 3은 미분화 갑상선암 세포에서 방사성 요오드 섭취에 대한 화합물 18a의 효과를 나타낸 것이다.1 to 3 show the effect of compound 18a on radioactive iodine intake in undifferentiated thyroid cancer cells.
도 4 및 도 5는 미분화 갑상선암 세포에서 내생의 ERRγ 와 NIS mRNA 발현 조절에 대한 화합물 18a의 효과를 나타낸 것이다.4 and 5 show the effect of compound 18a on the regulation of endogenous ERRγ and NIS mRNA expression in undifferentiated thyroid cancer cells.
도 6 및 도 7은 미분화 갑상선암 세포에서 내생의 ERRγ 단백질 발현 조절에 대한 화합물 18a의 효과를 나타낸 것이다.6 and 7 show the effect of compound 18a on the regulation of endogenous ERRγ protein expression in undifferentiated thyroid cancer cells.
도 8 및 도 9는 미분화 갑상선암 세포에서 화합물 18a-유도된 MAP 키나아제 활성을 나타낸 것이다.8 and 9 show Compound 18a-induced MAP kinase activity in undifferentiated thyroid cancer cells.
도 10 및 도 11은 PD98059 또는 U0126에 의한, 화합물 18a-처리된 미분화 갑상선암 세포에서 요오드 섭취의 저해 정도를 나타낸 것이다.10 and 11 show the degree of inhibition of iodine intake in Compound 18a-treated undifferentiated thyroid cancer cells by PD98059 or U0126.
도 12 및 도 13은 PD98059 또는 U0126에 의한, 활성화된 MAK 키나아제 시그널링의 반전 정도를 나타낸 것이다.12 and 13 show the degree of inversion of activated MAK kinase signaling by PD98059 or U0126.
도 14 및 도 15는 화합물 18a에 의한 미분화 갑상선암 세포에서 막-국재화된 NIS 단백질의 양의 증가 양상을 나타낸 것이다.14 and 15 show an increase in the amount of membrane-localized NIS protein in undifferentiated thyroid cancer cells by compound 18a.
도 16 및 도 17은 미분화 갑상선암 세포에 화합물 18a 처리 후 증가된 131I의 증가된 세포독성을 보여주는 결과이다.16 and 17 show the increased cytotoxicity of 131 I increased after treatment with Compound 18a on undifferentiated thyroid cancer cells.
도 18 내지 도 22는 ATC 종양모델에서 화합물 18a의 투여에 의한 방사성요오드 섭취에 대한 화합물 18a의 효과를 나타낸 것이다.18-22 show the effect of compound 18a on radioiodine intake by administration of compound 18a in an ATC tumor model.
이하, 본 발명에 대하여 보다 구체적으로 설명한다. 이 때 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely. Unless otherwise defined in the technical terms and scientific terms used at this time, have a meaning commonly understood by those of ordinary skill in the art to which the present invention belongs, unnecessarily obscure the subject matter of the present invention in the following description Description of known functions and configurations that may be omitted.
본 발명은 하기 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 제공한다:The present invention provides arylethene derivatives represented by Formula 1 below, prodrugs thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof:
[화학식 1][Formula 1]
Figure PCTKR2016010369-appb-I000003
Figure PCTKR2016010369-appb-I000003
상기 화학식 1에서, In Chemical Formula 1,
L은 (C6-C20)아릴렌, (C3-C20)헤테로아릴렌 또는 (C3-C20)융합헤테로고리이고;L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
R1은 (C3-C20)헤테로사이클로알킬, (C3-C20)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
R11 내지 R15는 각각 독립적으로 (C3-C20)헤테로사이클로알킬이고; R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl;
R16 및 R17는 각각 독립적으로 (C1-C20)알킬이고;R 16 and R 17 are each independently (C 1 -C 20) alkyl;
m은 1 내지 3의 정수이고;m is an integer from 1 to 3;
n은 0 또는 1의 정수이고;n is an integer of 0 or 1;
Ar은 (C6-C20)아릴 또는 (C3-C20)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C20)알킬, 할로(C1-C20)알킬, (C1-C20)알콕시, 니트로, 시아노, -NR21R22, (C1-C20)알킬카보닐옥시, (C1-C20)알킬카보닐아미노, 구아니디노, -SO2-R23 및 -OSO2-R24으로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
R21 및 R22는 각각 독립적으로 수소, (C1-C20)알킬설포닐 또는 (C3-C20)시클로알킬설포닐이고;R 21 and R 22 are each independently hydrogen, (C1-C20) alkylsulfonyl or (C3-C20) cycloalkylsulfonyl;
R23 및 R24는 각각 독립적으로 (C1-C20)알킬, 할로(C1-C20)알킬 또는 (C3-C20)시클로알킬이고;R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
R2는 히드록시, 할로겐, (C1-C20)알킬카보닐옥시 또는 (C1-C20)알킬설포닐옥시이고;R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C20)알킬, (C3-C20)사이클로알킬, (C2-C20)알케닐, 아미디노(amidino), (C1-C20)알콕시카보닐, 히드록시, 히드록시(C1-C20)알킬 및 디(C1-C20)알킬아미노(C1-C20)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
상기 헤테로사이클로알킬 및 헤테로아릴은 N, O 및 S로부터 선택되는 하나 이상의 헤테로 원자를 포함하며, 상기 헤테로사이클로알킬은 고리 내 탄소 원자 또는 질소 원자를 결합 부위로 갖는 포화 또는 불포화된 모노, 바이 또는 스피로 고리이다.The heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
본 발명에 따른 화학식 1의 아릴에텐 유도체는 신규한 화합물로서, ERRγ에 대한 매우 높은 억제 활성을 가지고 있어 ERRγ에 의해 매개되는 질환, 특히 비만, 당뇨, 고지혈증, 지방간 또는 동맥경화 등과 같은 대사성 질환의 치료제 및 예방제로 유용할 뿐만 아니라 망막병증을 예방하거나 치료하는데 유효성분으로 이용될 수 있다.The arylethene derivatives of the general formula (1) according to the present invention are novel compounds, which have very high inhibitory activity against ERRγ and are particularly effective for the diseases mediated by ERRγ, especially metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver or arteriosclerosis. In addition to being useful as a therapeutic and prophylactic agent, it can be used as an active ingredient in preventing or treating retinopathy.
또한, 본 발명에 따른 화학식 1의 아릴에텐 유도체는 내생의 ERRγ 단백질의 발현을 조절하여 MAP 키나아제(mitogen-activated protein kinase)를 조절하고, NIS(sodium iodide symporter)의 기능을 향상시켜 막-국재화된 NIS(membrane-localized NIS)를 증가시킴으로써 갑상선암의 치료시 방사성 요오드 섭취를 증진시킬 수 있다.In addition, the arylethene derivative of Formula 1 according to the present invention regulates MAP kinase (mitogen-activated protein kinase) by regulating the expression of endogenous ERRγ protein, and improves the function of sodium iodide symporter (NIS). Increasing membrane-localized NIS can enhance radioactive iodine intake in the treatment of thyroid cancer.
본 발명의 용어 “알킬”은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소 라디칼을 의미하는 것으로, 이러한 알킬 라디칼의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 헥실, 옥틸, 노닐 등을 포함하지만 이에 한정되지는 않는다.As used herein, the term "alkyl" refers to a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, examples of which alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl , Pentyl, hexyl, octyl, nonyl, and the like.
본 발명의 용어 “아릴”은 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 방향족 고리 1가의 유기 라디칼로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합고리계를 포함하며, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 포함한다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐(indenyl), 플루오레닐 등을 포함하지만, 이에 한정되지는 않는다. The term "aryl" of the present invention is an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by one hydrogen removal, each ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.
본 발명의 용어 “헤테로아릴”은 방향족 고리 골격 원자로서 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하고, 나머지 방향족 고리 골격 원자가 탄소인 아릴 그룹인 헤테로방향족고리 1가의 라디칼을 의미하는 것으로, 5 내지 6원 단환 헤테로아릴, 및 하나 이상의 벤젠환과 축합된 다환식 헤테로아릴이며, 부분적으로 포화될 수도 있다. 또한, 본 발명에서의 헤테로아릴은 하나 이상의 헤테로아릴이 단일결합으로 연결된 형태도 포함한다. 상기 헤테로아릴기의 예는 피롤릴, 피라졸릴, 퀴놀릴, 이소퀴놀릴, 피리딜, 피리미디닐, 옥사졸릴, 티아졸릴, 티아디아졸릴, 트리아졸릴, 이미다졸릴, 벤조이미다졸릴, 이소옥사졸릴, 벤조이소옥사졸릴, 티오펜일, 벤조티오펜일, 퓨릴, 벤조퓨릴 등을 포함하지만, 이에 한정되지는 않는다. As used herein, the term “heteroaryl” means a heteroaromatic monovalent radical which is an aryl group containing 1 to 4 heteroatoms selected from N, O and S as an aromatic ring skeleton atom and the remaining aromatic ring skeleton atoms are carbons. 5 to 6 membered monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected by a single bond. Examples of such heteroaryl groups include pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzoimidazolyl, iso Oxazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, and the like.
본 발명의 용어 “아릴렌” 및 “헤테로아릴렌”은 방향족고리 및 헤테로방향족고리의 2가 라디칼을 의미한다. As used herein, the terms “arylene” and “heteroarylene” mean divalent radicals of aromatic rings and heteroaromatic rings.
본 발명의 용어 “융합헤테로고리”는 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하는 비방향족 헤테로고리와 방향족고리가 융합된 융합고리의 2가 라디칼을 의미하는 것으로, 융합헤테로고리 내 탄소 원자 또는 질소 원자를 결합 부위로 갖는다. 상기 융합헤테로고리의 예는 인돌린, 디하이드로벤조퓨란, 디하이드로벤조티오펜 등을 포함하지만, 이에 한정되는 않는다.As used herein, the term “fused heterocycle” refers to a divalent radical of a fused ring in which an aromatic ring is fused with a non-aromatic heterocycle including 1 to 4 heteroatoms selected from N, O, and S. It has a carbon atom or a nitrogen atom in a ring as a bonding site. Examples of the fused heterocycle include, but are not limited to, indolin, dihydrobenzofuran, dihydrobenzothiophene, and the like.
본 발명의 용어 “헤테로사이클로알킬”은 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하는 비방향족 헤테로고리의 1가 라디칼로, 상기 비방향족 헤테로고리는 포화 또는 불포화된 단일고리, 다중고리 또는 스피로고리 형태를 모두 포함하며, 헤테로원자 또는 탄소원자를 통해 결합될 수 있다. 이러한 헤테로사이클로알킬 라디칼의 예로는 아지리딘, 피롤리딘, 아제티딘, 피페리딘, 테트라하이드로피리딘, 피페라진, 모폴린, 티오모폴린, 3-아자바이사이클로[3.1.0]헥산, 옥타하이드로피롤로[3,4-c]피롤, 2,7-다이아자스피로[4.4]노난, 2-아자스피로[4.4]노난 등의 비방향족 헤테로고리의 1가 라디칼을 포함할 수 있다.As used herein, the term “heterocycloalkyl” refers to a monovalent radical of a non-aromatic heterocycle including 1 to 4 heteroatoms selected from N, O and S, wherein the non-aromatic heterocycle is a saturated or unsaturated monocyclic ring, It includes both polycyclic or spirochroic forms and can be linked via heteroatoms or carbon atoms. Examples of such heterocycloalkyl radicals are aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo [3.1.0] hexane, octahydro Monovalent radicals of non-aromatic heterocycles such as pyrrolo [3,4-c] pyrrole, 2,7-diazaspiro [4.4] nonane, 2-azaspiro [4.4] nonane and the like.
본 발명의 용어 “할로” 또는 “할로겐”은 불소, 염소, 브롬 또는 요오드 원자를 의미한다. The term "halo" or "halogen" in the present invention means fluorine, chlorine, bromine or iodine atoms.
본 발명의 용어 “할로알킬”은 하나이상의 할로겐으로 치환된 알킬을 의미하며, 일례로 트리플루오로메틸 등을 들 수 있다.The term "haloalkyl" of the present invention means alkyl substituted with one or more halogens, and examples thereof include trifluoromethyl and the like.
본 발명의 용어 “알케닐”은 두 개 이상의 탄소 원자들 사이에 하나 이상의 이중 결합을 포함하는 직쇄 또는 분쇄의 불포화 탄화수소 1가 라디칼로, 구체적으로 에테닐, 프로펜일, 프로프-1-엔-2일, 1-부테닐, 2-부테닐, 이소부틸레닐, 1-펜테닐, 2-펜테닐, 3-메틸-1-부테닐, 2-메틸-2-부테닐, 2,3-디메틸-2-부테닐 등을 포함하지만 이에 한정되지는 않는다.The term "alkenyl" of the present invention is a straight chain or branched unsaturated hydrocarbon monovalent radical comprising one or more double bonds between two or more carbon atoms, specifically, ethenyl, propenyl, prop-1-ene- 2 days, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl -2-butenyl and the like.
본 발명의 용어 “알콕시”는 -O-알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알콕시 라디칼의 예는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시 등을 포함하지만 이에 한정되지는 않는다.The term “alkoxy” in the present invention means an —O-alkyl radical, where “alkyl” is as defined above. Examples of such alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.
본 발명의 용어 “알킬카보닐옥시”는 -OC(=O)알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알킬카보닐옥시 라디칼의 예는 메틸카보닐옥시, 에틸카보닐옥시, 이소프로필카보닐옥시, 프로필카보닐옥시, 부틸카보닐옥시, 이소부틸카보닐옥시, t-부틸카보닐옥시 등을 포함하지만 이에 한정되지는 않는다.As used herein, the term “alkylcarbonyloxy” refers to an —OC (═O) alkyl radical, where “alkyl” is as defined above. Examples of such alkylcarbonyloxy radicals include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy and the like. But it is not limited thereto.
본 발명의 용어 “알킬카보닐아미노”는 -NHC(=O)알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알킬카보닐아미노 라디칼의 예는 메틸카보닐아미노, 에틸카보닐아미노, 이소프로필카보닐아미노, 프로필카보닐아미노, 부틸카보닐아미노, 이소부틸카보닐아미노, t-부틸카보닐아미노 등을 포함하지만 이에 한정되지는 않는다.The term “alkylcarbonylamino” in the present invention means an —NHC (═O) alkyl radical, where “alkyl” is as defined above. Examples of such alkylcarbonylamino radicals include methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, propylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, t-butylcarbonylamino, and the like. But it is not limited thereto.
본 발명의 용어 “알콕시카보닐”은 -C(=O)알콕시 라디칼을 의미하는 것으로, 여기서 ‘알콕시’는 상기 정의한 바와 같다. 이러한 알콕시카보닐 라디칼의 예는 메톡시카보닐, 에톡시카보닐, 이소프로폭시카보닐, 프로폭시카보닐, 부톡시카보닐, 이소부톡시카보닐, t-부톡시카보닐 등을 포함하지만 이에 한정되지는 않는다.The term "alkoxycarbonyl" of the present invention means an -C (= O) alkoxy radical, where "alkoxy" is as defined above. Examples of such alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, and the like. It is not limited.
본 발명의 용어 “사이클로알킬”은 하나 이상의 고리로 구성된 1가의 포화 카보사이클릭 라디칼을 의미한다. 사이클로알킬 라디칼의 예는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 등을 포함하지만, 이에 한정되지는 않는다.As used herein, the term “cycloalkyl” means a monovalent saturated carbocyclic radical composed of one or more rings. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
본 발명의 용어 “알킬설포닐”은 -SO2-알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알킬설포닐 라디칼의 예는 메틸설포닐, 에틸설포닐 등을 포함하지만 이에 한정되지는 않는다.The term "alkylsulfonyl" in the present invention means an -SO 2 -alkyl radical, where 'alkyl' is as defined above. Examples of such alkylsulfonyl radicals include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
본 발명의 용어 “사이클로알킬설포닐”은 -SO2-사이클로알킬 라디칼을 의미하는 것으로, 여기서 ‘사이클로알킬’은 상기 정의한 바와 같다. 이러한 사이클로알킬설포닐 라디칼의 예는 사이클로프로필설포닐, 사이클로헥실설포닐 등을 포함하지만 이에 한정되지는 않는다.The term “cycloalkylsulfonyl” in the present invention means an —SO 2 -cycloalkyl radical, where 'cycloalkyl' is as defined above. Examples of such cycloalkylsulfonyl radicals include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and the like.
본 발명의 용어 “알킬설포닐옥시”는 -OSO2-알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알킬설포닐옥시 라디칼의 예는 메틸설포닐옥시, 에틸설포닐옥시 등을 포함하지만 이에 한정되지는 않는다.The term "alkylsulfonyloxy" in the present invention means an -OSO 2 -alkyl radical, where 'alkyl' is as defined above. Examples of such alkylsulfonyloxy radicals include, but are not limited to, methylsulfonyloxy, ethylsulfonyloxy, and the like.
본 발명의 용어 “히드록시알킬”은 하나 이상의 히드록시로 치환된 알킬을 의미하며, 일례로 히드록시메틸 등을 들 수 있다.The term "hydroxyalkyl" in the present invention means alkyl substituted with one or more hydroxy, and examples thereof include hydroxymethyl and the like.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 하기 화학식 2 내지 5로 표시될 수 있다:In the arylethene derivative according to one embodiment of the present invention, the arylethene derivative may be represented by the following Chemical Formulas 2 to 5:
[화학식 2][Formula 2]
Figure PCTKR2016010369-appb-I000004
Figure PCTKR2016010369-appb-I000004
[화학식 3][Formula 3]
Figure PCTKR2016010369-appb-I000005
Figure PCTKR2016010369-appb-I000005
[화학식 4][Formula 4]
Figure PCTKR2016010369-appb-I000006
Figure PCTKR2016010369-appb-I000006
[화학식 5][Formula 5]
Figure PCTKR2016010369-appb-I000007
Figure PCTKR2016010369-appb-I000007
상기 화학식 2 내지 5에서,
Figure PCTKR2016010369-appb-I000008
는 단일결합 또는 이중결합을 나타내고; R1, Ar 및 R2는 상기 화학식 1에서의 정의와 동일하다.In Chemical Formulas 2 to 5,
Figure PCTKR2016010369-appb-I000008
Represents a single bond or a double bond; R 1 , Ar and R 2 are the same as defined in the formula (1).
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 R1은 (C3-C10)헤테로사이클로알킬, (C3-C10)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R11 내지 R15는 각각 독립적으로 (C3-C10)헤테로사이클로알킬이고; R16 및 R17는 각각 독립적으로 (C1-C10)알킬이고; m은 1 내지 3의 정수이고; n은 0 또는 1의 정수이고; Ar은 (C6-C12)아릴 또는 (C3-C12)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R2는 히드록시, 플루오르, (C1-C10)알킬카보닐옥시 또는 (C1-C10)알킬설포닐옥시이고; 상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있다.In an arylethene derivative according to an embodiment of the present invention, R 1 is (C3-C10) heterocycloalkyl, (C3-C10) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ; R 11 to R 15 are each independently (C 3 -C 10) heterocycloalkyl; R 16 and R 17 are each independently (C 1 -C 10) alkyl; m is an integer from 1 to 3; n is an integer of 0 or 1; Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10 Alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1-C10) alkyl Carbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyloxy or (C3 -C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of; R 2 is hydroxy, fluorine, (C 1 -C 10) alkylcarbonyloxy or (C 1 -C 10) alkylsulfonyloxy; Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, It may be further substituted with one or more selected from the group consisting of (C1-C10) alkoxycarbonyl, hydroxy (C1-C10) alkyl and di (C1-C10) alkylamino (C1-C10) alkyl.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 바람직하게 상기 R1은 (C3-C10)헤테로사이클로알킬 또는 -O-(CH2)m-R11이고, R11은 (C3-C10)헤테로사이클로알킬이고, m은 1 내지 3의 정수이고, 상기 R1 및 R11의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있다.In the arylethene derivative according to an embodiment of the present invention, preferably, R 1 is (C3-C10) heterocycloalkyl or -O- (CH 2 ) m -R 11 , and R 11 is (C3-C10) Heterocycloalkyl, m is an integer from 1 to 3, wherein the heterocycloalkyl of R 1 and R 11 is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino (amidino), (C1-C10) alkoxycarbonyl, hydroxy (C1-C10) alkyl and di (C1-C10) alkylamino (C1-C10) alkyl, and may be further substituted with one or more selected from the group consisting of .
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 더욱 바람직하게 상기 R1 및 R11 내지 R15의 헤테로사이클로알킬은 각각 독립적으로 하기 구조에서 선택될 수 있다:In the arylethene derivative according to an embodiment of the present invention, more preferably the heterocycloalkyl of R 1 and R 11 to R 15 may be each independently selected from the following structures:
Figure PCTKR2016010369-appb-I000009
Figure PCTKR2016010369-appb-I000009
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 보다 바람직하게 하기 화학식 6으로 표시될 수 있다:In the arylethene derivative according to an embodiment of the present invention, the arylethene derivative may be more preferably represented by the following Formula 6:
[화학식 6][Formula 6]
Figure PCTKR2016010369-appb-I000010
Figure PCTKR2016010369-appb-I000010
상기 화학식 6에서,In Chemical Formula 6,
R1은 (C3-C10)헤테로사이클로알킬 또는 -O-(CH2)m-R11이고;R 1 is (C3-C10) heterocycloalkyl or —O— (CH 2 ) m —R 11 ;
R11은 (C3-C10)헤테로사이클로알킬이고;R 11 is (C3-C10) heterocycloalkyl;
m은 1 내지 3의 정수이고; m is an integer from 1 to 3;
상기 R1 및 R11의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;The heterocycloalkyl of R 1 and R 11 is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, hydroxide May be further substituted with one or more selected from the group consisting of oxy (C 1 -C 10) alkyl and di (C 1 -C 10) alkylamino (C 1 -C 10) alkyl;
Ar은 (C6-C12)아릴 또는 (C3-C12)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10 Alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1-C10) alkyl Carbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyloxy or (C3 -C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of;
R2는 히드록시, 플루오르, (C1-C10)알킬카보닐옥시 또는 (C1-C10)알킬설포닐옥시이다.R 2 is hydroxy, fluorine, (C 1 -C 10) alkylcarbonyloxy or (C 1 -C 10) alkylsulfonyloxy.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 R1 및 R11은 독립적으로 하기 구조에서 선택되는 헤테로사이클로알킬일 수 있다:In the arylethene derivative according to one embodiment of the present invention, R 1 and R 11 may be heterocycloalkyl independently selected from the following structures:
Figure PCTKR2016010369-appb-I000011
Figure PCTKR2016010369-appb-I000011
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 Ar은 (C6-C12)아릴이고, 상기 Ar의 아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있다.In an arylethene derivative according to an embodiment of the present invention, Ar is (C6-C12) aryl, and aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1 -C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyl It may be further substituted with one or more selected from the group consisting of oxy or (C3-C10) cycloalkylsulfonyloxy.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 R2는 히드록시일 수 있다.In the arylethene derivative according to one embodiment of the present invention, R 2 may be hydroxy.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 보다 바람직하게 상기 R2는 히드록시이고, R1은 하기 구조에서 선택되는 헤테로사이클로알킬일 수 있다:In the arylethene derivative according to one embodiment of the present invention, more preferably, R 2 is hydroxy and R 1 may be heterocycloalkyl selected from the following structures:
Figure PCTKR2016010369-appb-I000012
Figure PCTKR2016010369-appb-I000012
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 보다 바람직하게 상기 R2는 히드록시이고, R1은 -O-(CH2)m-R11이고, m은 1 또는 2의 정수이고, R11은 하기 구조에서 선택되는 헤테로사이클로알킬일 수 있다:In the arylethene derivative according to the embodiment of the present invention, more preferably, R 2 is hydroxy, R 1 is -O- (CH 2 ) m -R 11 , m is an integer of 1 or 2, R 11 may be heterocycloalkyl selected from the following structures:
Figure PCTKR2016010369-appb-I000013
Figure PCTKR2016010369-appb-I000013
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C1-C10)알콕시카보닐 또는 히드록시(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl or hydroxy (C 1 -C 10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 보다 더 바람직하게 상기 Ar은 (C6-C12)아릴이고, 상기 Ar의 아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R2는 히드록시이고, R1은 하기 구조에서 선택되는 헤테로사이클로알킬일 수 있다:In an arylethene derivative according to an embodiment of the present invention, even more preferably Ar is (C6-C12) aryl, and aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1- C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) Amino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10 ) Alkylsulfonyloxy or (C3-C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of; R 2 is hydroxy and R 1 may be heterocycloalkyl selected from the following structures:
Figure PCTKR2016010369-appb-I000014
Figure PCTKR2016010369-appb-I000014
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 보다 더 바람직하게 상기 Ar은 (C6-C12)아릴이고, 상기 Ar의 아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R2는 히드록시이고, R1은 -O-(CH2)m-R11이고, m은 1 또는 2의 정수이고, R11은 하기 구조에서 선택되는 헤테로사이클로알킬일 수 있다:In an arylethene derivative according to an embodiment of the present invention, even more preferably Ar is (C6-C12) aryl, and aryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1- C10) alkyl, (C1-C10) alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) Amino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10 ) Alkylsulfonyloxy or (C3-C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of; R 2 is hydroxy, R 1 is —O— (CH 2 ) m —R 11 , m is an integer of 1 or 2, and R 11 may be heterocycloalkyl selected from the following structures:
Figure PCTKR2016010369-appb-I000015
Figure PCTKR2016010369-appb-I000015
상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C1-C10)알콕시카보닐 또는 히드록시(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl or hydroxy (C 1 -C 10) alkyl; L is O or S.
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 구체적으로 하기 구조로부터 선택될 수 있으며, 이에 한정되는 것은 아니다.In the arylethene derivative according to an embodiment of the present invention, the arylethene derivative may be specifically selected from the following structures, but is not limited thereto.
Figure PCTKR2016010369-appb-I000016
Figure PCTKR2016010369-appb-I000016
Figure PCTKR2016010369-appb-I000017
Figure PCTKR2016010369-appb-I000017
Figure PCTKR2016010369-appb-I000018
Figure PCTKR2016010369-appb-I000018
Figure PCTKR2016010369-appb-I000019
Figure PCTKR2016010369-appb-I000019
Figure PCTKR2016010369-appb-I000020
Figure PCTKR2016010369-appb-I000020
Figure PCTKR2016010369-appb-I000021
Figure PCTKR2016010369-appb-I000021
Figure PCTKR2016010369-appb-I000022
Figure PCTKR2016010369-appb-I000022
Figure PCTKR2016010369-appb-I000023
Figure PCTKR2016010369-appb-I000023
Figure PCTKR2016010369-appb-I000024
Figure PCTKR2016010369-appb-I000024
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 바람직하게 하기 구조로부터 선택될 수 있다.In the arylethene derivative according to one embodiment of the present invention, the arylethene derivative may be preferably selected from the following structures.
Figure PCTKR2016010369-appb-I000025
Figure PCTKR2016010369-appb-I000025
Figure PCTKR2016010369-appb-I000026
Figure PCTKR2016010369-appb-I000026
Figure PCTKR2016010369-appb-I000027
Figure PCTKR2016010369-appb-I000027
Figure PCTKR2016010369-appb-I000028
Figure PCTKR2016010369-appb-I000028
Figure PCTKR2016010369-appb-I000029
Figure PCTKR2016010369-appb-I000029
Figure PCTKR2016010369-appb-I000030
Figure PCTKR2016010369-appb-I000030
Figure PCTKR2016010369-appb-I000031
Figure PCTKR2016010369-appb-I000031
Figure PCTKR2016010369-appb-I000032
Figure PCTKR2016010369-appb-I000032
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 더욱 바람직하게 하기 구조로부터 선택될 수 있다.In the arylethene derivative according to one embodiment of the present invention, the arylethene derivative may be more preferably selected from the following structures.
Figure PCTKR2016010369-appb-I000033
Figure PCTKR2016010369-appb-I000033
Figure PCTKR2016010369-appb-I000034
Figure PCTKR2016010369-appb-I000034
Figure PCTKR2016010369-appb-I000035
Figure PCTKR2016010369-appb-I000035
Figure PCTKR2016010369-appb-I000036
Figure PCTKR2016010369-appb-I000036
Figure PCTKR2016010369-appb-I000037
Figure PCTKR2016010369-appb-I000037
Figure PCTKR2016010369-appb-I000038
Figure PCTKR2016010369-appb-I000038
Figure PCTKR2016010369-appb-I000039
Figure PCTKR2016010369-appb-I000039
본 발명의 일실시예에 따른 아릴에텐 유도체에서, 상기 아릴에텐 유도체는 더욱 더 바람직하게 하기 구조로부터 선택될 수 있다.In the arylethene derivative according to an embodiment of the present invention, the arylethene derivative may be even more preferably selected from the following structures.
Figure PCTKR2016010369-appb-I000040
Figure PCTKR2016010369-appb-I000040
Figure PCTKR2016010369-appb-I000041
Figure PCTKR2016010369-appb-I000041
Figure PCTKR2016010369-appb-I000042
Figure PCTKR2016010369-appb-I000042
Figure PCTKR2016010369-appb-I000043
Figure PCTKR2016010369-appb-I000043
Figure PCTKR2016010369-appb-I000044
Figure PCTKR2016010369-appb-I000044
Figure PCTKR2016010369-appb-I000045
Figure PCTKR2016010369-appb-I000045
Figure PCTKR2016010369-appb-I000046
Figure PCTKR2016010369-appb-I000046
본 발명에 따른 아릴에텐 유도체는 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 프로드럭, 용매화물 및 약제학적으로 허용 가능한 염의 형태로 만들어 사용할 수 있으므로, 상기의 프로드럭, 용매화물 및 약제학적으로 허용 가능한 염 역시 본 발명의 범위에 속한다. 또한, 상기 아릴에텐 유도체는 키랄 탄소를 갖고 있어서, 그의 입체이성질체가 존재하며, 이러한 입체이성질체 역시 본 발명의 범주 내에 포함된다. The arylethene derivatives according to the present invention can be used in the form of prodrugs, solvates and pharmaceutically acceptable salts to enhance in vivo absorption or increase solubility, so that the above prodrugs, solvates and pharmaceuticals Salts which are also acceptable are also within the scope of the present invention. In addition, the arylethene derivative has a chiral carbon, so that stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.
본 발명에 따른 아릴에텐 유도체는 그 치환체의 종류에 따라 알려진 다양한 방법으로 제조될 수 있는데, 일례로 하기 반응식 1 내지 21를 예시하였으며, 하기의 제조방법이 본 발명의 아릴에텐 유도체를 제조하는 방법을 한정하는 것은 아니다. 더 자세한 내용은 하기 실시예 1 내지 121에서 설명된다. 하기 반응식 1 내지 21에 제시된 제조방법은 예시일 뿐이며, 특정의 치환체에 따라 당업자에 의해 용이하게 변형될 수 있음은 당업자에게 자명할 것이다.The arylethene derivatives according to the present invention may be prepared by various methods known according to the type of substituents thereof. For example, the following Reaction Schemes 1 to 21 are exemplified. It does not limit the method. Further details are described in Examples 1 to 121 below. It will be apparent to those skilled in the art that the preparation methods shown in Schemes 1 to 21 are merely exemplary and can be easily modified by those skilled in the art according to specific substituents.
[반응식 1] Scheme 1
Figure PCTKR2016010369-appb-I000047
Figure PCTKR2016010369-appb-I000047
[반응식 2] Scheme 2
Figure PCTKR2016010369-appb-I000048
Figure PCTKR2016010369-appb-I000048
[반응식 3] Scheme 3
Figure PCTKR2016010369-appb-I000049
Figure PCTKR2016010369-appb-I000049
[반응식 4] Scheme 4
Figure PCTKR2016010369-appb-I000050
Figure PCTKR2016010369-appb-I000050
[반응식 5]Scheme 5
Figure PCTKR2016010369-appb-I000051
Figure PCTKR2016010369-appb-I000051
[반응식 6] Scheme 6
Figure PCTKR2016010369-appb-I000052
Figure PCTKR2016010369-appb-I000052
[반응식 7] Scheme 7
Figure PCTKR2016010369-appb-I000053
Figure PCTKR2016010369-appb-I000053
[반응식 8]Scheme 8
Figure PCTKR2016010369-appb-I000054
Figure PCTKR2016010369-appb-I000054
[반응식 9]Scheme 9
Figure PCTKR2016010369-appb-I000055
Figure PCTKR2016010369-appb-I000055
[반응식 10] Scheme 10
Figure PCTKR2016010369-appb-I000056
Figure PCTKR2016010369-appb-I000056
[반응식 11]Scheme 11
Figure PCTKR2016010369-appb-I000057
Figure PCTKR2016010369-appb-I000057
[반응식 12] Scheme 12
Figure PCTKR2016010369-appb-I000058
Figure PCTKR2016010369-appb-I000058
[반응식 13]Scheme 13
Figure PCTKR2016010369-appb-I000059
Figure PCTKR2016010369-appb-I000059
[반응식 14]Scheme 14
Figure PCTKR2016010369-appb-I000060
Figure PCTKR2016010369-appb-I000060
[반응식 15] Scheme 15
Figure PCTKR2016010369-appb-I000061
Figure PCTKR2016010369-appb-I000061
[반응식 16]Scheme 16
Figure PCTKR2016010369-appb-I000062
Figure PCTKR2016010369-appb-I000062
[반응식 17]Scheme 17
Figure PCTKR2016010369-appb-I000063
Figure PCTKR2016010369-appb-I000063
[반응식 18]Scheme 18
[반응식 19]Scheme 19
Figure PCTKR2016010369-appb-I000065
Figure PCTKR2016010369-appb-I000065
[반응식 20] Scheme 20
Figure PCTKR2016010369-appb-I000066
Figure PCTKR2016010369-appb-I000066
[반응식 21]Scheme 21
Figure PCTKR2016010369-appb-I000067
Figure PCTKR2016010369-appb-I000067
또한, 본 발명은 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 ERRγ 저해제 조성물을 제공한다.The present invention also provides an ERRγ inhibitor composition comprising an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 유효성분으로서 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 포함하고, 추가로 약제학적으로 하용 가능한 담체를 포함하는 ERRγ에 의해 매개되는 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention includes an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and further includes a pharmaceutically acceptable carrier. It provides a pharmaceutical composition for the prevention or treatment of diseases mediated by ERRγ.
상기한 바와 같이, 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염은 ERRγ에 대한 높은 억제 활성을 나타내므로, 이들을 유효성분으로 포함하는 약제학적 조성물은 ERRγ에 의해 매개되는 질환, 예를 들어 비만, 당뇨, 고지혈증, 지방간 또는 동맥경화 등과 같은 대사성 질환의 치료 또는 예방에 유용하게 사용될 수 있다.As described above, the arylethene derivatives of formula (1), their prodrugs, their solvates, their stereoisomers or their pharmaceutically acceptable salts exhibit high inhibitory activity against ERRγ, and therefore, as an active ingredient The pharmaceutical composition may be usefully used for the treatment or prevention of ERRγ-mediated diseases such as obesity, diabetes, hyperlipidemia, fatty liver or atherosclerosis.
또한, 본 발명은 ERRγ의 활성을 효과적으로 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 함유하는 망막병증의 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention is a retinopathy containing an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient capable of effectively inhibiting the activity of ERRγ. It provides a pharmaceutical composition for the prophylaxis or treatment of.
상기 "망막병증(retinopathy)"은 눈의 망막에 만성 또는 급성에 의한 손상으로 발병하는 질환이다. 이러한 망막병증은 계속 진행중인 염증 및 혈관 리모델링(vascular remodeling)을 수반할 수 있다. 또한, 망막병증은 당뇨병 또는 고혈압과 같은 전신 질환의 시각적 발현으로 나타나기도 한다. 이러한 망막병증의 종류로는 당뇨망막병증(diabetic retinopathy) 및 미숙아 망막병증(retinopathy of prematurity, ROP) 등이 있다. The "retinopathy" is a disease caused by chronic or acute damage to the retina of the eye. Such retinopathy may involve ongoing inflammation and vascular remodeling. Retinopathy also manifests itself as a visual manifestation of systemic diseases such as diabetes or hypertension. Types of retinopathy include diabetic retinopathy and retinopathy of prematurity (ROP).
여기서, 당뇨망막병증은 전신 질환인 당뇨병에 의한 말초 순환 장애에 따라 장애가 생겨 시력 감소가 발생하는 눈의 합병증을 의미한다. 당뇨망막병증은 초기에는 증상이 없으나, 황반부의 침범이 일어나게 되면서 시력 저하를 나타낸다. 당뇨망막병증은 미세혈관류, 정맥확장, 망막출혈, 망막경색, 황반부종, 신생혈관, 초자체출혈, 견인성 막 등 다양한 병리학적 특징을 수반하여, 이러한 현상이 안저 증상으로 관찰되면 당뇨망막병증으로 진단된다. 당뇨망막병증은 상기와 같은 다양한 증상이 복합적으로 수반되어 발병하는 질환으로, 이 중 하나의 증상을 완화시킬 수 있다고 해서 질환의 치료를 가져올 수 있는지는 불분명한 면이 있다.Here, diabetic retinopathy refers to a complication of eyes in which a disorder occurs due to peripheral circulation disorder caused by systemic diabetes mellitus, resulting in decreased vision. Diabetic retinopathy is initially asymptomatic, but the macular invasion develops, resulting in decreased vision. Diabetic retinopathy is accompanied by various pathological features such as microvascular perfusion, venous dilatation, retinal hemorrhage, retinal infarction, macular edema, neovascularization, vitreous hemorrhage, and tractional membrane. Diagnosed. Diabetic retinopathy is a disease that is caused by a combination of various symptoms as described above, and it is unclear whether treatment of the disease can be caused by being able to alleviate one of these symptoms.
또한, 미숙아 망막병증은 미숙아, 특히 저체중출생아에게서 발생할 수 있는 증식성 망막병증이다. 출생 시 망막의 혈관이 완전히 형성되지 않은 미숙아에게 출생 후 혈관형성 과정에 장애가 발생하면 망막의 혈관형성부위와 혈관무형성 부위의 경계에서 비정상적인 섬유혈관증식이 발생하며, 이에 의해 망막이 박리되면서 최종적으로 실명을 초래할 수 있다.In addition, prematurity retinopathy is a proliferative retinopathy that can occur in premature infants, especially underweight babies. In premature infants whose blood vessels are not fully formed at birth, abnormal blood vessel proliferation occurs at the boundary between the retinal angiogenesis site and the angiogenesis site, resulting in abnormal retinal detachment. May result.
본 발명에 따른 아릴에텐 유도체는 약제학적으로 허용되는 염의 형태로 사용할 수 있으며, 약제학적으로 허용되는 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 트리플루오로아세트산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레산, 말론산, 만델산, 신남산, 스테아르산, 팔미트산, 글리콜산, 글루탐산 타르타르산, 글루콘산, 락트산, 푸마르산, 락토비온산, 아스코르브산, 살리실산, 또는 아세틸살리실산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염, 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 등을 포함한다. The arylethene derivatives according to the present invention can be used in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salts can be prepared by conventional methods in the art, for example hydrochloric acid, bromic acid. Salts with inorganic acids such as sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, mandelic acid, cinnamic acid Salts with organic acids such as stearic acid, palmitic acid, glycolic acid, glutamic acid tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, ascorbic acid, salicylic acid, or acetylsalicylic acid (aspirin), glycine, alanine, vanillin, iso Salts with amino acids such as leucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid, Salts with sulfonic acids such as benzenesulfonic acid, toluenesulfonic acid and the like, metal salts by reaction with alkali metals such as sodium and potassium, salts with ammonium ions and the like.
본 발명의 아릴에텐 유도체는 용매화된 형태, 예를 들어 수화된 형태 및 비용매화 형태로 존재할 수 있으며, 본 발명에 따른 아릴에텐 유도체의 용매화물은 제약 활성을 갖는 모든 용매화된 형태를 포함하는 것이다. 즉, 본 발명의 아릴에텐 유도체를 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음, 유리산 또는 유리염기를 가한 후에 결정화되거나 또는 재결정화되어 수화물을 포함한 용매화물이 형성될 수 있다. 따라서, 본 발명의 신규 화합물로서 동결건조와 같은 방법으로 제조 가능한 다양한 양의 물 함유 화합물 이외에 수화물을 비롯한 화학 양론적 용매화물도 포함한다.The arylethene derivatives of the present invention may exist in solvated forms, for example hydrated forms and unsolvated forms, and solvates of arylethene derivatives according to the present invention are suitable for all solvated forms having pharmaceutical activity. It is to include. That is, the arylethene derivative of the present invention is dissolved in a solvent that can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized or recrystallized after adding a free acid or free base to hydrate the hydrate. Including solvates may be formed. Accordingly, the novel compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization.
본 발명의 아릴에텐 유도체는 키랄 중심을 가질 수 있고, 라세메이트, 라세미 혼합물 및 개개의 거울상 이성질체 또는 부분 입체이성질체로서 존재할 수 있다. 이러한 이성질체는 통상의 방법에 의해 분리되거나 분해될 수 있으며 임의의 소정 이성질체는 통상의 합성법에 의해 또는 입체특이적 또는 비대칭적 합성에 의해 수득할 수 있다. 이러한 모든 이성질체 형 및 이들의 혼합물은 본 발명의 범위 내에 포함된다.The arylethene derivatives of the present invention may have a chiral center and may exist as racemates, racemic mixtures and as individual enantiomers or diastereomers. Such isomers may be separated or resolved by conventional methods and any given isomer may be obtained by conventional synthesis or by stereospecific or asymmetric synthesis. All such isomeric forms and mixtures thereof are included within the scope of the present invention.
본 발명의 아릴에텐 유도체는 인간 또는 동물의 체내에서 분해되어 본 발명의 화합물을 제공하는 프로드럭의 형태로 투여될 수 있다. 프로드럭은 모 화합물의 물리적 및(또는) 약동학적 프로파일을 변경 또는 개선하는데 사용될 수 있고 모 화합물이 프로드럭을 형성하도록 유도될 수 있는 적합한 기 또는 치환체를 함유할 경우 형성될 수 있다. The arylethene derivatives of the present invention can be administered in the form of prodrugs that degrade in the human or animal body to provide the compounds of the present invention. Prodrugs can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be induced to form the prodrug.
또한, 본 발명의 약제학적 조성물은 상기 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염에 통상의 무독성 약제학적으로 허용 가능한 담체 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 환제, 경연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭서제(elixirs) 등의 경구투여용 제제 또는 정맥내, 피하, 설하, 근육내 또는 안내 투약용 멸균성 수성 또는 오일상 용제의 비경구투여용 제제로 제제화할 수 있다. In addition, the pharmaceutical composition of the present invention is a non-toxic pharmaceutically acceptable carrier which is conventional in the arylethene derivative represented by Formula 1, prodrug thereof, solvate thereof, stereoisomer or pharmaceutically acceptable salt thereof, and Oral preparations or intravenous administrations such as tablets, pills, hard capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. It may be formulated as a parenteral preparation of sterile aqueous or oily solvents for subcutaneous, sublingual, intramuscular or intraocular administration.
본 발명의 약제학적 조성물에 사용될 수 있는 약제학적으로 허용 가능한 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및/또는 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are those commonly used in the preparation of lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and / or mineral oil, It is not limited to this.
본 발명의 약제학적 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 있으며, 이러한 부형제의 비율 및 성질은 선택된 정제의 용해도 및 화학적 특성, 선택된 투여경로 및 표준 약제 실무에 의해 결정될 수 있다. 부형제의 예로는 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that may be used in the pharmaceutical compositions of the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. The proportion and nature of the excipient can be determined by the solubility and chemical properties of the selected tablet, the chosen route of administration and standard pharmaceutical practice. Examples of excipients include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, alginine acid, Sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
또한, 본 발명의 약제학적 조성물은 비경구 투여 형태로 제형화될 수도 있는데, 이러한 경우 정맥 내 투여, 복강 내 투여, 근육 내 투여, 피하 투여 또는 국부 투여 등을 이용할 수 있으며, 망막병증에 대한 치료제인 점에서 안구 투여 등을 이용할 수 있으나, 이에 제한되지 않는다. 이 때, 상기 비경구 투여용 제형으로 제제화하기 위하여, 상기 약제학적 조성물은 유효 성분, 즉, 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염이 안정제 또는 완충제와 함께 물에서 혼합되어 용액 또는 현탁액으로 제조되고, 이러한 용액 또는 현탁액이 앰플 또는 바이알의 단위 투여형으로 제조될 수 있다.In addition, the pharmaceutical composition of the present invention may be formulated in a parenteral dosage form, in which case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration or topical administration may be used, and a therapeutic agent for retinopathy In this regard, eye administration may be used, but is not limited thereto. At this time, in order to formulate into the formulation for parenteral administration, the pharmaceutical composition is an active ingredient, that is, an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable thereof. Salts are mixed in water with stabilizers or buffers to form solutions or suspensions, which solutions or suspensions may be prepared in unit dosage forms of ampoules or vials.
또한, 본 발명의 약제학적 조성물은 멸균되거나, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.In addition, the pharmaceutical composition of the present invention may be sterile, or may further include adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and further include other therapeutically useful substances. Or may be formulated according to conventional methods of mixing, granulating or coating.
또한, 본 발명에 따른 약제학적 조성물에서 유효성분인 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염은 사람을 포함하는 포유류에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있다. 일반적으로 하루에 0.001 내지 100 ㎎/㎏(체중), 바람직하게는 0.01 내지 100 ㎎/㎏(체중)의 유효량으로 상기 약제학적 조성물에 포함될 수 있고, 이러한 약제학적 조성물은 1 일 1 회 또는 2 회 이상 분할되어 경구 또는 비경구적 경로를 통해 투여될 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다. In addition, the arylethene derivative represented by the formula (1), the prodrug, the solvate thereof, the stereoisomer or the pharmaceutically acceptable salt thereof represented by Formula 1, which is an active ingredient in the pharmaceutical composition according to the present invention, may be used for mammals including humans. Dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Generally, the pharmaceutical composition may be included in the pharmaceutical composition in an effective amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 100 mg / kg body weight, and such pharmaceutical composition may be once or twice a day. The biphasic can be administered via oral or parenteral routes. However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
또한, 본 발명은 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 약제학적으로 하용 가능한 담체를 포함하고, 방사성 요오드와 병용하여 사용되는 갑상선암 치료용 약제학적 조성물을 제공한다.In addition, the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, which can specifically inhibit ERRγ transcriptional activity, and a pharmaceutical It provides a pharmaceutical composition for the treatment of thyroid cancer, comprising a carrier which can be used as is, and used in combination with radioactive iodine.
또한, 본 발명은 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있는 상기 화학식 1의 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 방사성 요오드를 포함하는 갑상선암 치료용 키트를 제공한다.In addition, the present invention provides an arylethene derivative of Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a radioactive iodine which can specifically inhibit ERRγ transcriptional activity. It provides a kit for treating thyroid cancer.
본 발명에 따른 아릴에텐 유도체는 내생의 ERRγ 단백질의 발현을 조절하여 MAP 키나아제(mitogen-activated protein kinase)를 조절하고, NIS(sodium iodide symporter)의 기능을 향상시켜 막-국재화된 NIS(membrane-localized NIS)를 증가시킴으로써 갑상선암의 치료시 방사성 요오드 섭취를 증진시킬 수 있다.The arylethene derivative according to the present invention regulates MAP kinase (mitogen-activated protein kinase) by regulating the expression of endogenous ERRγ protein, and improves the function of sodium iodide symporter (NIS) to improve membrane-localized NIS (membrane). Increasing -localized NIS may improve radioactive iodine intake in the treatment of thyroid cancer.
이하, 실시예 및 실험예를 통해 본 발명을 상세히 설명한다. 단, 하기의 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples.
[실시예 1] (E)-tert-butyl 4-(2-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (6a)의 제조 Example 1 (E) -tert-butyl 4- (2- (4- (5-methoxy-5-oxo-2-phenyl-1- (4- (pivaloyloxy) phenyl) pent-1-en-1 Preparation of -yl) phenoxy) ethyl) piperazine-1-carboxylate ( 6a )
Figure PCTKR2016010369-appb-I000068
Figure PCTKR2016010369-appb-I000068
단계 1: [4-[4-(2,2-Step 1: [4- [4- (2,2- 다이메틸프로파노일옥시Dimethylpropanoyloxy )) 벤조일Benzoyl ]페닐] 2,2-] Phenyl] 2,2- 다이메틸프로파노에이트Dimethylpropanoate ( ( A-1A-1 )의 제조Manufacturing
4,4-하이드록시벤조페논 (10 g, 46.6 mmol)을 디클로로메탄 140 mL, 테트라하이드로퓨란 40 mL 에 용해시킨 뒤 피발로일 클로라이드 (19.7 g, 186 mmol)와 트리에틸아민 (26 mL, 186 mmol)을 천천히 첨가한 뒤 상온에서 12시간 반응하였다. 반응액에 포화탄산수소나트륨과 디클로로메탄을 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 A-1 16 g (91%)을 얻었다.4,4-hydroxybenzophenone (10 g, 46.6 mmol) was dissolved in 140 mL of dichloromethane and 40 mL of tetrahydrofuran, followed by pivaloyl chloride (19.7 g, 186 mmol) and triethylamine (26 mL, 186 mmol) was slowly added and reacted at room temperature for 12 hours. Saturated sodium hydrogen carbonate and dichloromethane were further added to the reaction mixture, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 16 g (91%) of the title compound A-1 .
단계 2: [4-(4-하이드록시벤조일)페닐] 2,2-다이메틸프로파노에이트 (Step 2: [4- (4-hydroxybenzoyl) phenyl] 2,2-dimethylpropanoate ( A-2A-2 )의 제조Manufacturing
화합물 A-1 (12.4 g, 32.3 mmol) 과 포타슘카보네이트 (2.2 g, 16.2 mmol) 을 메탄올 (360 mL), 디클로로메탄 (60 mL) 에 녹인 뒤 상온에서 12시간 반응하였다. 반응액에 1 M 시트릭산 수용액 (16.2 mL, 16.2 mmol)을 첨가한 뒤, 에틸아세테이트로 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 A- 2 5.6 g (58%)을 얻었다. Compound A-1 (12.4 g, 32.3 mmol) and potassium carbonate (2.2 g, 16.2 mmol) were dissolved in methanol (360 mL) and dichloromethane (60 mL) and reacted at room temperature for 12 hours. 1 M aqueous citric acid solution (16.2 mL, 16.2 mmol) was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified using column chromatography to obtain 5.6 g (58%) of the title compound A- 2 .
단계 3: (E)-5-[4-(2,2-Step 3: (E) -5- [4- (2,2- 다이메틸프로파노일옥시Dimethylpropanoyloxy )페닐]-5-(4-) Phenyl] -5- (4- 하이드록시페닐Hydroxyphenyl )-4-페닐-펜-4-이노에이트 () -4-phenyl-phen-4-inoate ( A-3A-3 )의 제조Manufacturing
테트라하이드로퓨란 (130 mL) 에 아연 (8.8 g, 134 mmol) 을 넣고 0 ℃로 온도를 낮춘 뒤 티타늄클로라이드 (7.35 mL, 67 mmol)을 천천히 첨가하였다. 반응액을 60 ℃에서 두시간 가열한 뒤 화합물 A-2 (5 g, 16.8 mmol) 과 메틸 3-벤조일프로피오네이트 (4.8 g, 25.1 mmol) 을 넣어주었다. 반응액을 50 ℃에서 1시간 가열하였다. 반응혼합물을 10% 포타슘카보네이트 수용액에 붓고 30분간 교반시킨 뒤 셀라이트를 이용해 여과시켰다. 여액을 에틸아세테이트로 추출한 뒤 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 A-3 5.4 g (70%)을 얻었다.Zinc (8.8 g, 134 mmol) was added to tetrahydrofuran (130 mL), the temperature was lowered to 0 ° C., and titanium chloride (7.35 mL, 67 mmol) was added slowly. After heating the reaction solution at 60 ° C. for 2 hours, Compound A-2 (5 g, 16.8 mmol) and methyl 3-benzoylpropionate (4.8 g, 25.1 mmol) were added thereto. The reaction solution was heated at 50 ° C. for 1 hour. The reaction mixture was poured into 10% aqueous potassium carbonate solution, stirred for 30 minutes, and filtered using celite. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 5.4 g (70%) of the title compound A-3 .
단계 4: (E)-Step 4: (E)- terttert -butyl 4-(2-(4-(5--butyl 4- (2- (4- (5- methoxymethoxy -5--5- oxooxo -2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (-2-phenyl-1- (4- (pivaloyloxy) phenyl) pent-1-en-1-yl) phenoxy) ethyl) piperazine-1-carboxylate ( A-4A-4 )의 제조 Manufacturing
디클로로메탄 (3 mL)에 화합물 A-3 (0.05 g, 0.11 mmol), 2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethanol (30 mg, 0.13 mmol), 트리페닐포스핀 (86 mg, 0.33 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 다이아이소프로필 아조다이카복실레이트 (0.064 mL, 0.33 mmol)을 천천히 첨가하였다. 15분뒤 상온으로 온도를 올려주고 12시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 A-4 73 mg (99%)을 얻었다.In dichloromethane (3 mL) Compound A-3 (0.05 g, 0.11 mmol), 2- (4- (tert-Butyloxycarbonyl) piperazin-1-yl) ethanol (30 mg, 0.13 mmol), triphenylphosphine (86 mg, 0.33 mmol) was added and the temperature was lowered to 0 ° C., and diisopropyl azodicarboxylate (0.064 mL, 0.33 mmol) was added slowly. After 15 minutes, the temperature was raised to room temperature and stirred for 12 hours. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 73 mg (99%) of the title compound A-4 .
단계 5: (Z)-4-Step 5: (Z) -4- (5-hydroxy-1-(4-(2-(4-(5-hydroxy-1- (4- (2- (4- (( terttert -- ButyloxycarbonylButyloxycarbonyl )) piperazinpiperazin -1-yl)ethoxy)phenyl)-2-phenylpent-1-en-1-yl)phenol (-1-yl) ethoxy) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 6a6a )의 제조Manufacturing
테트라하이드로퓨란 (10 mL)에 화합물 C (0.34 g, 0.05 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 1M 리튬알루미늄하이드록사이드 (LiAlH4, 1.5 mL, 1.51 mmol)을 천천히 첨가하였다. 상온으로 온도를 올려주고 1시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 6a 0.28 g (99%)을 얻었다.Compound C (0.34 g, 0.05 mmol) was added to tetrahydrofuran (10 mL), and the temperature was lowered to 0 ° C., followed by slowly adding 1M lithium aluminum hydroxide (LiAlH 4 , 1.5 mL, 1.51 mmol). The temperature was raised to room temperature and stirred for 1 hour. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 0.28 g (99%) of the title compound 6a .
[실시예 2 내지 13][Examples 2 to 13]
상기 실시예 1의 방법에 따라 화합물 6b 내지 6m을 제조하였다. 화합물 6b 내지 6m은 실시예 1의 단계 4에서 2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethanol을 상이한 에탄올로 대체하는 점을 제외하고는 동일한 공정으로 제조하였다. 제조된 화합물 6a 내지 6m의 동정자료를 하기 표 1에 기재하였다.Compounds 6b to 6m were prepared according to the method of Example 1 above. Compounds 6b to 6m were prepared by the same process except that 2- (4- (tert-Butyloxycarbonyl) piperazin-1-yl) ethanol was replaced with different ethanol in Step 4 of Example 1. Identification data of the prepared compounds 6a to 6m are shown in Table 1 below.
[표 1]TABLE 1
Figure PCTKR2016010369-appb-I000069
Figure PCTKR2016010369-appb-I000069
Figure PCTKR2016010369-appb-I000070
Figure PCTKR2016010369-appb-I000070
Figure PCTKR2016010369-appb-I000071
Figure PCTKR2016010369-appb-I000071
[실시예 14] (Z)-4-(5-hydroxy-2-phenyl-1-(4-(2-(piperazin-1-yl)ethoxy)phenyl)pent-1-en-1-yl)phenol 2hydrochloride salt (7a)의 제조Example 14 (Z) -4- (5-hydroxy-2-phenyl-1- (4- (2- (piperazin-1-yl) ethoxy) phenyl) pent-1-en-1-yl) phenol Preparation of 2hydrochloride salt ( 7a )
Figure PCTKR2016010369-appb-I000072
Figure PCTKR2016010369-appb-I000072
디클로로메탄 (5 mL)에 화합물 6a (28 mg, 0.05 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 트리플루오로아세트산 (0.08 mL, 1.00 mmol)을 첨가하였다. 상온으로 온도를 올려주고 1시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용하여 정제한 다음, 메탄올:디클로로메탄 (1:1)에 녹이고 0 ℃로 온도를 낮춰 1M HCl 수용액을 천천히 가한 다음, 감압증류하여 목적화합물 7a 4 mg (17%)을 얻었다.Compound 6a (28 mg, 0.05 mmol) was added to dichloromethane (5 mL), and the temperature was lowered to 0 ° C., followed by addition of trifluoroacetic acid (0.08 mL, 1.00 mmol). The temperature was raised to room temperature and stirred for 1 hour. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. A residue was obtained by evaporating the solvent under reduced pressure purified using column chromatography, and then methanol: dichloromethane (1: 1) lowering the temperature to 0 ℃ added a 1M HCl solution slowly, and then distilled under reduced pressure to the desired compound dissolved in 7a 4 mg (17%) were obtained.
1H-NMR(CD3OD, 400MHz) δ 7.16-7.07 (m, 5H), 7.01 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.31 (t, J = 4.2 Hz, 2H), 3.66 (m, 10H), 3.41 (t, J = 6.8 Hz, 2H), 2.51 (m, 2H), 1.54 (m, 2H). MS (ESI) m/z: 459 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.16-7.07 (m, 5H), 7.01 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.31 (t, J = 4.2 Hz, 2H), 3.66 (m, 10H), 3.41 (t, J = 6.8 Hz, 2H), 2.51 (m, 2H), 1.54 (m, 2H ). MS (ESI) m / z: 459 [M + H] + .
[실시예 15] (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride salt (13a)의 제조Example 15 (E) -5- (4- (2- (aziridin-1-yl) ethoxy) phenyl) -5- (4-bromophenyl) -4-phenylpent-4-en-1-ol hydrochloride salt Preparation of ( 13a )
Figure PCTKR2016010369-appb-I000073
Figure PCTKR2016010369-appb-I000073
단계 1: (4-bromophenyl)(4-methoxyphenyl)methanone (Step 1: (4-bromophenyl) (4-methoxyphenyl) methanone ( B-1B-1 )의 제조Manufacturing
디클로로메탄 (90 mL)에 4-브로모벤조일 클로라이드 (8.2 g, 50.9 mmol)과 알루미늄 클로라이드 (6.1 g, 50.9 mmol)을 녹인 뒤, 아니졸 (5 g, 46.2 mmol)을 천천히 첨가하였다. 3시간 동안 교반시킨 뒤 0 ℃로 온도를 낮추고 1N HCl (50 mL)을 넣어주었다. 물층은 에틸아세테이트를 부가하여 추출하고, 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 B-1 11 g (99%)을 얻었다.4-bromobenzoyl chloride (8.2 g, 50.9 mmol) and aluminum chloride (6.1 g, 50.9 mmol) were dissolved in dichloromethane (90 mL), followed by the slow addition of anisol (5 g, 46.2 mmol). After stirring for 3 hours, the temperature was lowered to 0 ° C. and 1N HCl (50 mL) was added thereto. The water layer was extracted by adding ethyl acetate, dried over anhydrous Na 2 SO 4 , and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 11 g (99%) of the title compound B-1 .
단계 2: (4-bromophenyl)(4-hydroxyphenyl)methanone (Step 2: (4-bromophenyl) (4-hydroxyphenyl) methanone ( B-2B-2 )의 제조Manufacturing
톨루엔 (80 mL)에 화합물 B-1 (10 g, 34.3 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 알루미늄 클로라이드 (11.5 g, 86 mmol)을 천천히 첨가하였다. 4시간 동안 70 ℃에서 가열하였다. 반응액을 상온으로 식힌 뒤 1N 염산을 넣고 에틸아세테이트를 부가하여 추출하였다. 유기층은 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 B- 2 8.1 g (85%)을 얻었다.Compound B-1 (10 g, 34.3 mmol) was added to toluene (80 mL), the temperature was lowered to 0 ° C., and aluminum chloride (11.5 g, 86 mmol) was added slowly. Heated at 70 ° C. for 4 hours. After the reaction solution was cooled to room temperature, 1N hydrochloric acid was added thereto, and ethyl acetate was added to extract the mixture. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 8.1 g (85%) of the title compound B- 2 .
단계 3: (E)-methyl 5-(4-Step 3: (E) -methyl 5- (4- bromophenylbromophenyl )-5-(4-) -5- (4- hydroxyphenylhydroxyphenyl )-4-)-4- phenylpentphenylpent -4-enoate (-4-enoate ( B-3B-3 )의 제조Manufacturing
상기 실시예 1의 단계 3과 동일한 방법으로 목적화합물 B- 3 0.61 g (39%)을 얻었다. In the same manner as in Step 3 of Example 1 0.61 g (39%) of the title compound B- 3 was obtained.
단계 4: (E)-methyl 5-(4-(2-(Step 4: (E) -methyl 5- (4- (2- ( aziridinaziridin -1--One- ylyl )) ethoxyethoxy )phenyl)-5-(4-bromophenyl)-4-phenylpent-4-enoate () phenyl) -5- (4-bromophenyl) -4-phenylpent-4-enoate ( B-4B-4 )의 제조Manufacturing
화합물 B- 3와 2-(aziridin-1-yl)ethanol을 이용하여 상기 실시예 1의 단계 4와 동일한 방법으로 목적화합물 B-4 44 mg (54%)을 얻었다. In the same manner as in Step 4 of Example 1 using Compound B- 3 and 2- (aziridin-1-yl) ethanol 44 mg (54%) of the target compound B-4 were obtained.
단계 5: (E)-5-(4-(2-(Step 5: (E) -5- (4- (2- ( aziridinaziridin -1--One- ylyl )) ethoxyethoxy )phenyl)-5-(4-) phenyl) -5- (4- bromophenylbromophenyl )-4-phenylpent-4-en-1-ol hydrochloride salt () -4-phenylpent-4-en-1-ol hydrochloride salt ( 13a13a )의 제조Manufacturing
테트라하이드로퓨란 (2 mL)에 화합물 B-4 (44 mg, 0.09 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 1M 다이아이소부틸알루미늄 하이드라이드 (0.26 mL, 0.26 mmol)을 천천히 첨가하였다. 상온으로 온도를 올려주고 1시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 13a 0.3 mg (0.7%)을 얻었다.Compound B-4 (44 mg, 0.09 mmol) was added to tetrahydrofuran (2 mL), and the temperature was lowered to 0 ° C., and 1M diisobutylaluminum hydride (0.26 mL, 0.26 mmol) was slowly added thereto. The temperature was raised to room temperature and stirred for 1 hour. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 0.3 mg (0.7%) of the title compound 13a .
[실시예 16 내지 18][Examples 16 to 18]
상기 실시예 15의 방법에 따라 화합물 13b 내지 13d을 제조하였다. 화합물 13b 내지 13d 은 실시예 15의 단계 4에서 2-(aziridin-1-yl)ethanol을 상이한 에탄올로 대체하는 점을 제외하고는 동일한 공정으로 제조하였다. 제조된 화합물 13a 내지 13d의 동정자료를 하기 표 2에 기재하였다.Compounds 13b to 13d were prepared according to the method of Example 15 above. Compounds 13b to 13d were prepared by the same process except that 2- (aziridin-1-yl) ethanol was replaced with different ethanol in step 4 of Example 15. Identification data of the prepared compounds 13a to 13d are shown in Table 2 below.
[표 2]TABLE 2
Figure PCTKR2016010369-appb-I000074
Figure PCTKR2016010369-appb-I000074
[실시예 19] (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride salt (18t)의 제조Example 19 (E) -5- (4- (2- (aziridin-1-yl) ethoxy) phenyl) -5- (4-bromophenyl) -4-phenylpent-4-en-1-ol hydrochloride salt Preparation of ( 18t )
Figure PCTKR2016010369-appb-I000075
Figure PCTKR2016010369-appb-I000075
단계 1: 메틸 5-(4-(피발로일옥시)페닐)펜트-4-이노에이트(Step 1: methyl 5- (4- (pivaloyloxy) phenyl) pent-4-inoate ( C-1C-1 )의 제조Manufacturing
4-아이오도페닐 피발레이트 (2 g, 6.6 mmol), 염화구리(I) (0.13 g, 0.66 mmol), 비스(트리페닐포스핀)팔라듐(II) 다이클로라이드 (PdCl2(PPh3)2, 0.23 g, 0.33 mmol), 메틸 펜트-4-이노에이트(methyl pent-4-ynoate) (0.74 g, 0.66 mmol)을 트리에틸아민 (15 mL)에 용해시킨 뒤 50 ℃에서 12시간 반응하였다. 반응액을 감압 농축한 뒤 컬럼크로마토그래피법을 이용하여 목적화합물 C- 1 1.1 g (58%) 얻었다.4-iodophenyl pivalate (2 g, 6.6 mmol), copper chloride (I) (0.13 g, 0.66 mmol), bis (triphenylphosphine) palladium (II) dichloride (PdCl 2 (PPh 3 ) 2 , 0.23 g, 0.33 mmol) and methyl pent-4-ynoate (0.74 g, 0.66 mmol) were dissolved in triethylamine (15 mL) and reacted at 50 ° C. for 12 hours. The reaction solution was concentrated under reduced pressure and the target compound C- 1 1.1 g (58%) was obtained by column chromatography.
단계 2: (E)-Step 2: (E)- terttert -부틸 3-(4-(5--Butyl 3- (4- (5- 메톡시Methoxy -5-옥소-2-페닐-1-(4-(-5-oxo-2-phenyl-1- (4- ( 피발로일옥시Pivaloyloxy )페닐)펜트-1-엔-1-일)페닐)아제티딘-1-카르복실레이트() Phenyl) pent-1-en-1-yl) phenyl) azetidine-1-carboxylate ( C-2C-2 )의 제조Manufacturing
tert-부틸 3-(4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보란-2-일)페닐)아제티딘-1-카르복실레이트 (0.27 g, 0.75 mmol), 화합물 C-1 (0.14 g, 0.5 mmol), 아이오도벤젠 (84 μL, 0.75 mmol)을 DMF (8 mL), 물 (4 mL)에 용해시킨 뒤 0.025 M PdCl2(PhCN)2 (0.2 mL, 5 μmol)을 넣고 45 ℃에서 10분 가열하였다. 세슘카르보네이트 (0.24 g, 0.75 mmol)를 넣고 12시간 45 ℃에서 가열하였다. 반응이 종결되면 반응액에 소금물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 C-2 81 mg (27%)를 얻었다.tert-butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenyl) azetidine-1-carboxylate (0.27 g, 0.75 mmol ), Compound C-1 (0.14 g, 0.5 mmol), iodobenzene (84 μL, 0.75 mmol) are dissolved in DMF (8 mL), water (4 mL), and then 0.025 M PdCl 2 (PhCN) 2 (0.2 mL, 5 μmol) was added and heated at 45 ° C. for 10 minutes. Cesium carbonate (0.24 g, 0.75 mmol) was added thereto and heated at 45 ° C. for 12 hours. Upon completion of the reaction, brine and ethyl acetate were further added to the reaction solution to extract the organic layer. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 81 mg (27%) of the title compound C-2 .
단계 3: Step 3: terttert -butyl (E)-3-(4-(5--butyl (E) -3- (4- (5- hydroxyhydroxy -1-(4--1- (4- hydroxyphenylhydroxyphenyl )-2-phenylpent-1-en-1-yl)phenyl)azetidine-1-carboxylate() -2-phenylpent-1-en-1-yl) phenyl) azetidine-1-carboxylate ( 18t18t )의 제조Manufacturing
테트라하이드로퓨란 (2 mL)에 화합물 C-2 (0.021 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 1M 리튬알루미늄하이드라이드 또는 다이아이소부틸알루미늄 하이드라이드 또는 리튬보로하이드라이드 (0.024 mL, 0.024 mmol)을 첨가하였다. 상온으로 온도를 올려주고 1시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용하여 정제한 다음, 메탄올:디클로로메탄(1:1)에 녹이고 0 ℃로 온도를 낮춰 1M HCl 수용액을 천천히 가한 다음, 감압증류하여 목적화합물 18t 24 mg (78%)을 얻었다.Compound C-2 (0.021 mmol) was added to tetrahydrofuran (2 mL) and the temperature was lowered to 0 ° C., followed by 1M lithium aluminum hydride or diisobutyl aluminum hydride or lithium borohydride (0.024 mL, 0.024 mmol). Was added. The temperature was raised to room temperature and stirred for 1 hour. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. A residue was obtained by evaporating the solvent under reduced pressure purified using column chromatography, and then methanol: dichloromethane (1: 1) The preparation of the compound to lower the temperature to 0 ℃ added a 1M HCl solution slowly, and then distilled under reduced pressure and dissolved in 18t 24 mg (78%) were obtained.
[실시예 20 내지 39][Examples 20 to 39]
상기 실시예 19의 방법을 이용하여 화합물 18a 내지 18s 및 18u을 제조하였다. 제조된 화합물 18a 내지 18u의 동정자료를 하기 표 3에 기재하였다. Compounds 18a-18s and 18u were prepared using the method of Example 19 above. Identification data of the prepared compounds 18a to 18u are shown in Table 3 below.
[표 3]TABLE 3
Figure PCTKR2016010369-appb-I000076
Figure PCTKR2016010369-appb-I000076
Figure PCTKR2016010369-appb-I000077
Figure PCTKR2016010369-appb-I000077
Figure PCTKR2016010369-appb-I000078
Figure PCTKR2016010369-appb-I000078
Figure PCTKR2016010369-appb-I000079
Figure PCTKR2016010369-appb-I000079
Figure PCTKR2016010369-appb-I000080
Figure PCTKR2016010369-appb-I000080
[실시예 40] (E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-en-1-ol (20a)의 제조Example 40 Preparation of (E) -5- (4-bromophenyl) -4-phenyl-5- (4- (piperazin-1-yl) phenyl) pent-4-en-1-ol ( 20a )
Figure PCTKR2016010369-appb-I000081
Figure PCTKR2016010369-appb-I000081
단계 1: methyl (E)-5-(4-Step 1: methyl (E) -5- (4- bromophenylbromophenyl )-4-phenyl-5-(4-() -4-phenyl-5- (4- ( piperazinpiperazin -1-yl)phenyl)pent-4-enoate (-1-yl) phenyl) pent-4-enoate ( D-D- 22 )의)of 제조 Produce
디클로로메탄 (2 mL)에 화합물 D-1 (6 mg, 0.01 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 트리플로로아세트산 (0.05 mL, 0.65 mmol)을 천천히 첨가하였다. 상온으로 온도를 올려주고 12시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 D-2 5 mg (99%)을 얻었다.Compound D-1 (6 mg, 0.01 mmol) was added to dichloromethane (2 mL) and the temperature was lowered to 0 ° C., followed by the slow addition of trifluoroacetic acid (0.05 mL, 0.65 mmol). The temperature was raised to room temperature and stirred for 12 hours. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 5 mg (99%) of the title compound D-2 .
단계 2: (E)-5-(4-Step 2: (E) -5- (4- bromophenylbromophenyl )-4-phenyl-5-(4-() -4-phenyl-5- (4- ( piperazinpiperazin -1-yl)phenyl)pent-4-en-1-ol (-1-yl) phenyl) pent-4-en-1-ol ( 20a20a )의 제조Manufacturing
화합물 D- 2을 이용하여 상기 실시예 19의 단계 3과 동일한 방법으로 목적화합물 20a 7 mg (41%)을 얻었다.In the same manner as in Step 3 of Example 19, using Compound D- 2 7 mg (41%) of the title compound 20a was obtained.
[실시예 41 내지 51][Examples 41 to 51]
상기 실시예 40의 방법을 이용하여 화합물 20b 내지 20l을 제조하였다. 제조된 화합물 20a 내지 20l의 동정자료를 하기 표 4에 기재하였다.Compounds 20b to 20l were prepared using the method of Example 40. Identification data of the prepared compounds 20a to 20l are shown in Table 4 below.
[표 4]TABLE 4
Figure PCTKR2016010369-appb-I000082
Figure PCTKR2016010369-appb-I000082
Figure PCTKR2016010369-appb-I000083
Figure PCTKR2016010369-appb-I000083
Figure PCTKR2016010369-appb-I000084
Figure PCTKR2016010369-appb-I000084
[실시예 52] (E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2-phenylpent-1-en-1-yl)phenol (22a)의 제조Example 52 of (E) -4- (5-hydroxy-1- (4- (1-isopropylazetidin-3-yl) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 22a ) Produce
Figure PCTKR2016010369-appb-I000085
Figure PCTKR2016010369-appb-I000085
단계 1: methyl (E)-5-(4-(1-Step 1: methyl (E) -5- (4- (1- isopropylazetidinisopropylazetidin -3--3- ylyl )phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate () phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( E-2E-2 )의 제조Manufacturing
디클로로에탄 (3 mL)에 화합물 E-1 (0.03 g, 0.06 mmol), 아세톤 (0.14 mL, 1.9 mmol), 소듐트리아세톡시보로하이드라이드 (NaBH(OAc)3, 41 mg, 0.19 mmol)을 넣고 상온에서 1시간 동안 교반시켰다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 E- 2 18 mg (54%)을 얻었다.To dichloroethane (3 mL) add compound E-1 (0.03 g, 0.06 mmol), acetone (0.14 mL, 1.9 mmol), sodium triacetoxyborohydride (NaBH (OAc) 3 , 41 mg, 0.19 mmol) Stirred at room temperature for 1 hour. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 18 mg (54%) of the title compound E- 2 .
단계 2: (E)-4-(5-Step 2: (E) -4- (5- hydroxyhydroxy -1-(4-(1--1- (4- (1- isopropylazetidinisopropylazetidin -3--3- ylyl )phenyl)-2-phenylpent-1-en-1-yl)phenol () phenyl) -2-phenylpent-1-en-1-yl) phenol ( 22a22a )의 제조Manufacturing
화합물 E- 2을 이용하여 상기 실시예 19의 단계 3과 동일한 방법으로 목적화합물 22a 4 mg (27%)을 얻었다.In the same manner as in Step 3 of Example 19, using Compound E- 2 4 mg (27%) of the title compound 22a was obtained.
[실시예 53 내지 82][Examples 53 to 82]
상기 실시예 52의 방법을 이용하여 화합물 22b 내지 22ae을 제조하였다. 제조된 화합물 22a 내지 22ae의 동정자료를 하기 표 5에 기재하였다.Compounds 22b to 22ae were prepared using the method of Example 52. Identification data of the prepared compounds 22a to 22ae are shown in Table 5 below.
[표 5]TABLE 5
Figure PCTKR2016010369-appb-I000086
Figure PCTKR2016010369-appb-I000086
Figure PCTKR2016010369-appb-I000087
Figure PCTKR2016010369-appb-I000087
Figure PCTKR2016010369-appb-I000088
Figure PCTKR2016010369-appb-I000088
Figure PCTKR2016010369-appb-I000089
Figure PCTKR2016010369-appb-I000089
Figure PCTKR2016010369-appb-I000090
Figure PCTKR2016010369-appb-I000090
Figure PCTKR2016010369-appb-I000091
Figure PCTKR2016010369-appb-I000091
Figure PCTKR2016010369-appb-I000092
Figure PCTKR2016010369-appb-I000092
[실시예 83] (Z)-5-(4-aminophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (26a)의 제조Example 83 Preparation of (Z) -5- (4-aminophenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -4-phenylpent-4-en-1-ol ( 26a )
Figure PCTKR2016010369-appb-I000093
Figure PCTKR2016010369-appb-I000093
메탄올 (0.5 mL), 테트라하이드로퓨란 (0.5 mL)에 화합물 F-1 (0.01 g, 0.02 mmol), 암모늄 클로라이드 (11 mg, 0.21 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 아연 (13 mg, 0.21 mmol)을 넣어주었다. 상온에서 12시간 동안 교반시켰다. 셀라이트를 이용해 여과한 뒤 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 26a 9 mg (99%)을 얻었다.Compound F-1 (0.01 g, 0.02 mmol) and ammonium chloride (11 mg, 0.21 mmol) were added to methanol (0.5 mL) and tetrahydrofuran (0.5 mL), and the temperature was reduced to 0 ° C., followed by zinc (13 mg, 0.21). mmol) was added. Stir at room temperature for 12 hours. After filtration through celite and distillation of the solvent under reduced pressure, the residue was purified by column chromatography to obtain 9 mg (99%) of the title compound 26a .
[실시예 84 내지 86][Examples 84 to 86]
상기 실시예 83의 방법을 이용하여 화합물 26b 내지 26d을 제조하였다. 제조된 화합물 26a 내지 26d의 동정자료를 하기 표 6에 기재하였다.Compounds 26b to 26d were prepared using the method of Example 83 above. Identification data of the prepared compounds 26a to 26d are shown in Table 6 below.
[표 6]TABLE 6
Figure PCTKR2016010369-appb-I000094
Figure PCTKR2016010369-appb-I000094
[실시예 87] (E)-N-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent-1-en-1-yl)phenyl)methanesulfonamide (27a)의 제조Example 87 (E) -N- (4- (5-hydroxy-1- (4- (4-isopropylpiperazin-1-yl) phenyl) -2-phenylpent-1-en-1-yl) phenyl) Preparation of methanesulfonamide ( 27a )
Figure PCTKR2016010369-appb-I000095
Figure PCTKR2016010369-appb-I000095
디클로로메탄 (2 mL)에 화합물 26b (5 mg, 10 μmol), 트리에틸아민 (3 μL, 0.02 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 메탄설포닐 클로라이드 (1 μL, 0.01 mmol)을 넣어주었다. 상온에서 12시간 동안 교반시켰다. 반응액에 포화탄산수소나트륨과 디클로로메탄을 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용하여 정제한 다음, 메탄올:디클로로메탄(1:1)에 녹이고 0 ℃로 온도를 낮춰 1M HCl 수용액을 천천히 가한 다음, 감압증류하여 목적화합물 27a 1 mg (17%)을 얻었다.Compound 26b (5 mg, 10 μmol) and triethylamine (3 μL, 0.02 mmol) were added to dichloromethane (2 mL), and the temperature was lowered to 0 ° C., followed by methanesulfonyl chloride (1 μL, 0.01 mmol). . Stir at room temperature for 12 hours. Saturated sodium hydrogen carbonate and dichloromethane were further added to the reaction mixture, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. A residue was obtained by evaporating the solvent under reduced pressure purified using column chromatography, and then methanol: dichloromethane (1: 1) lowering the temperature to 0 ℃ added a 1M HCl solution slowly, and then distilled under reduced pressure to the desired compound was dissolved in 27a 1 mg (17%) was obtained.
[실시예 87 내지 94][Examples 87 to 94]
상기 실시예 87의 방법을 이용하여 화합물 27b 내지 27h을 제조하였다. 제조된 화합물 27a 내지 27h의 동정자료를 하기 표 7에 기재하였다.Compounds 27b to 27h were prepared using the method of Example 87 above. Identification data of the prepared compounds 27a to 27h are shown in Table 7 below.
[표 7]TABLE 7
Figure PCTKR2016010369-appb-I000096
Figure PCTKR2016010369-appb-I000096
Figure PCTKR2016010369-appb-I000097
Figure PCTKR2016010369-appb-I000097
[실시예 95] (E)-4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent-1-en-1-yl)phenyl methanesulfonate (28a)의 제조Example 95 (E) -4- (5-hydroxy-1- (4- (4-isopropylpiperazin-1-yl) phenyl) -2-phenylpent-1-en-1-yl) phenyl methanesulfonate ( 28a ) Manufacture
Figure PCTKR2016010369-appb-I000098
Figure PCTKR2016010369-appb-I000098
디클로로메탄 (2 mL)에 화합물 G-1 (10 mg, 22 μmol), 다이아이소프로필에틸아민 (8 μL, 0.04 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 메탄설포닐 클로라이드 (3 μL, 0.02 mmol)을 넣어주었다. 상온에서 12시간 동안 교반시켰다. 반응액에 포화탄산수소나트륨과 디클로로메탄을 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 28a 1 mg (9%)을 얻었다.Dichloromethane (2 mL) was added Compound G-1 (10 mg, 22 μmol), diisopropylethylamine (8 μL, 0.04 mmol), and the temperature was lowered to 0 ° C. and methanesulfonyl chloride (3 μL, 0.02 mmol). ). Stir at room temperature for 12 hours. Saturated sodium hydrogen carbonate and dichloromethane were further added to the reaction mixture, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 1 mg (9%) of the target compound 28a .
[실시예 96 내지 101][Examples 96 to 101]
상기 실시예 95의 방법을 이용하여 화합물 28b 내지 28g을 제조하였다. 제조된 화합물 28a 내지 28g의 동정자료를 하기 표 8에 기재하였다.Compounds 28b to 28g were prepared using the method of Example 95 above. Identification data of the prepared compounds 28a to 28g are shown in Table 8 below.
[표 8]TABLE 8
Figure PCTKR2016010369-appb-I000099
Figure PCTKR2016010369-appb-I000099
Figure PCTKR2016010369-appb-I000100
Figure PCTKR2016010369-appb-I000100
[실시예 102] (E)-4-(5-hydroxy-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-phenylpent-1-en-1-yl)phenol (30a)의 제조Example 102 (E) -4- (5-hydroxy-1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 30a ) Preparation
Figure PCTKR2016010369-appb-I000101
Figure PCTKR2016010369-appb-I000101
단계 1: methyl (E)-5-(4-((4-Step 1: methyl (E) -5- (4-((4- methylpiperazinmethylpiperazin -1--One- ylyl )methyl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate () methyl) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( H-2H-2 )의 제조Manufacturing
디클로로에탄 (3 mL)에 화합물 H-1 (0.01 g, 0.02 mmol), 1-메틸피페라진 (7 μL, 0.06 mmol), 소듐트리아세톡시보로하이드라이드 (NaBH(OAc)3, 14 mg, 0.06 mmol)을 넣고 50 ℃ 에서 12시간 동안 가열하였다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 H- 2 12 mg (99%)을 얻었다.To dichloroethane (3 mL) Compound H-1 (0.01 g, 0.02 mmol), 1-methylpiperazine (7 μL, 0.06 mmol), sodium triacetoxyborohydride (NaBH (OAc) 3 , 14 mg, 0.06 mmol) was heated at 50 ° C. for 12 h. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 12 mg (99%) of the title compound H- 2 .
단계 2: (E)-4-(5-Step 2: (E) -4- (5- hydroxyhydroxy -1-(4-((4--1- (4-((4- methylpiperazinmethylpiperazin -1--One- ylyl )methyl)phenyl)-2-phenylpent-1-en-1-yl)phenol () methyl) phenyl) -2-phenylpent-1-en-1-yl) phenol ( 30a30a )의 제조Manufacturing
화합물 H- 2을 이용하여 상기 실시예 19의 단계 3과 동일한 방법으로 목적화합물 30a 2 mg (18%)을 얻었다.Use of a compound H- 2 to Example 19 step 3 to yield the target compound and 30a 2 mg (18%) in the same manner.
[실시예 103]Example 103
상기 실시예 102의 방법을 이용하여 화합물 30b을 제조하였다. 제조된 화합물 30a 내지 30b의 동정자료를 하기 표 9에 기재하였다.Compound 30b was prepared using the method of Example 102 above. Identification data of the prepared compounds 30a to 30b are shown in Table 9 below.
[표 9]TABLE 9
Figure PCTKR2016010369-appb-I000102
Figure PCTKR2016010369-appb-I000102
[실시예 104] (Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pent-1-en-1-yl)phenol (33)의 제조Example 104 (Z) -4- (5-hydroxy-2-phenyl-1- (1- (2- (pyrrolidin-1-yl) ethyl) indolin-5-yl) pent-1-en-1 Preparation of -yl) phenol ( 33 )
Figure PCTKR2016010369-appb-I000103
Figure PCTKR2016010369-appb-I000103
단계 1: methyl (Z)-5-(Step 1: methyl (Z) -5- ( indolinindolin -5--5- ylyl )-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate () -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( I-I- 22 )의)of 제조 Produce
화합물 I-1을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 I-2 0.2 g (99%)을 얻었다.0.2 g (99%) of the title compound I-2 was obtained by the same method as Step 1 of Example 40 using compound I-1 .
단계 2: methyl (Z)-4-phenyl-5-(4-(Step 2: methyl (Z) -4-phenyl-5- (4- ( pivaloyloxypivaloyloxy )phenyl)-5-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pent-4-enoate () phenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) indolin-5-yl) pent-4-enoate ( I-3I-3 )의 제조Manufacturing
디메틸포름아마이드 (1 mL)에 화합물 I-2 (20 mg, 0.04 mmol), 포타슘카보네이트 (17 mg, 0.12 mmol), 소듐아이오다이드 (0.06 mg, 0.414 μmol)을 넣고 상온에서 12시간 동안 교반시켰다. 반응액에 포화탄산수소나트륨과 에틸아세테이트를 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 I-3 3 mg (11%)을 얻었다.To dimethylformamide (1 mL) was added Compound I-2 (20 mg, 0.04 mmol), potassium carbonate (17 mg, 0.12 mmol), sodium iodide (0.06 mg, 0.414 μmol) and stirred at room temperature for 12 hours. . Saturated sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 3 mg (11%) of the title compound I-3 .
단계 3: (Z)-4-(5-Step 3: (Z) -4- (5- hydroxyhydroxy -2-phenyl-1-(1-(2-(-2-phenyl-1- (1- (2- ( pyrrolidinpyrrolidin -1-yl)ethyl)indolin-5-yl)pent-1-en-1-yl)phenol (-1-yl) ethyl) indolin-5-yl) pent-1-en-1-yl) phenol ( 3333 )의 제조Manufacturing
화합물 I-3을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 33 1 mg (55%)을 얻었다.Using compound I-3 , 1 mg (55%) of the title compound 33 was obtained by the same method as Step 5 of Example 1.
1H-NMR(CD3OD, 400MHz) δ 7.19-6.97 (m, 7H), 6.77 (d, J = 8.5 Hz, 2H), 6.64 (m, 2H), 6.41 (d, J = 8.7 Hz, 2H), 3.67 (m, 2H), 3.41 (m, 2H), 3.51 (m, 2H), 2.06 (m, 6H), 1.55 (m, 2H), 0.89 (m, 4H). MS (ESI) m/z: 469 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.19-6.97 (m, 7H), 6.77 (d, J = 8.5 Hz, 2H), 6.64 (m, 2H), 6.41 (d, J = 8.7 Hz, 2H ), 3.67 (m, 2H), 3.41 (m, 2H), 3.51 (m, 2H), 2.06 (m, 6H), 1.55 (m, 2H), 0.89 (m, 4H). MS (ESI) m / z: 469 [M + H] + .
[실시예 105] (Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)pent-1-en-1-yl)phenol (36)의 제조Example 105 (Z) -4- (5-hydroxy-2-phenyl-1- (1- (2- (piperidin-1-yl) ethyl) -1H-indol-5-yl) pent-1- Preparation of en-1-yl) phenol ( 36 )
Figure PCTKR2016010369-appb-I000104
Figure PCTKR2016010369-appb-I000104
단계 1: methyl (Z)-5-(1H-Step 1: methyl (Z) -5- (1H- indolindol -5--5- ylyl )-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate () -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( J-2J-2 )의 제조Manufacturing
화합물 J-1을 이용하여 상기 실시예 40의 단계 2과 동일한 방법으로 목적화합물 J-2 24 mg (99%)을 얻었다.24 mg (99%) of the target compound J-2 was obtained by the same method as Step 2 of Example 40 using compound J-1 .
단계 2: methyl (Z)-4-phenyl-5-(1-(2-(Step 2: methyl (Z) -4-phenyl-5- (1- (2- ( piperidinpiperidin -1--One- ylyl )ethyl)-1H-) ethyl) -1H- indolindol -5-yl)-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (-5-yl) -5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( J-3J-3 )의 제조Manufacturing
화합물 J- 2을 이용하여 상기 실시예 104의 단계 1과 동일한 방법으로 목적화합물 J-3 9 mg (31%)을 얻었다.Use of a compound J- 2 to Example 104 Step 1 in the same manner of the title compound J-3 9 mg (31% ).
단계 3: (Z)-4-(5-Step 3: (Z) -4- (5- hydroxyhydroxy -2-phenyl-1-(1-(2-(-2-phenyl-1- (1- (2- ( piperidinpiperidin -1--One- ylyl )ethyl)-1H-indol-5-yl)pent-1-en-1-yl)phenol () ethyl) -1H-indol-5-yl) pent-1-en-1-yl) phenol ( 3636 )의 제조Manufacturing
화합물 J-3을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 36 2 mg (18%)을 얻었다.Using compound J-3 , 2 mg (18%) of the target compound 36 was obtained by the same method as Step 5 of Example 1.
1H-NMR(CD3OD, 400MHz) δ 7.30-6.95 (m, 14H), 4.41 (m, 2H), 3.61 (m, 4H), 3.44 (m, 2H), 3.11 (m, 2H), 2.56 (m, 2H), 1.93 (m, 6H), 1.57 (m, 2H). MS (ESI) m/z: 481 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.30-6.95 (m, 14H), 4.41 (m, 2H), 3.61 (m, 4H), 3.44 (m, 2H), 3.11 (m, 2H), 2.56 (m, 2H), 1.93 (m, 6H), 1.57 (m, 2H). MS (ESI) m / z: 481 [M + H] + .
[실시예 106] (Z)-4-(1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (38a)의 제조Example 106 (Z) -4- (1- (4- (2- (3-azabicyclo [3.1.0] hexan-3-yl) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1- Preparation of en-1-yl) phenol ( 38a )
Figure PCTKR2016010369-appb-I000105
Figure PCTKR2016010369-appb-I000105
단계 1: methyl (E)-5-(4-(2-(3-Step 1: methyl (E) -5- (4- (2- (3- azabicyclo[3.1.0]hexanazabicyclo [3.1.0] hexan -3-yl)ethoxy)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (-3-yl) ethoxy) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( K-K- 22 )의)of 제조 Produce
디메틸포름아마이드 (1 mL)에 K-1 (10 mg, 0.02 mmol), 3-아자바이싸이클로[3,1,0]헥산 (7 mg, 0.06 mmol), 소듐아이오다이드 (0.3 mg, 2 μmol), 트리에틸아민 (11 μL, 0.08 mmol)을 넣고 80 ℃에서 12시간 동안 가열하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 K- 2 6 mg (53%)을 얻었다.Dimethylformamide (1 mL) in K-1 (10 mg, 0.02 mmol), 3-azabicyclo [3,1,0] hexane (7 mg, 0.06 mmol), sodium iodide (0.3 mg, 2 μmol) ), Triethylamine (11 μL, 0.08 mmol) was added and heated at 80 ° C. for 12 hours. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain the title compound K- 2 6 mg (53%).
단계 2: (Z)-4-(1-(4-(2-(3-Step 2: (Z) -4- (1- (4- (2- (3- azabicyclo[3.1.0]hexanazabicyclo [3.1.0] hexan -3--3- ylyl )) ethoxyethoxy )phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol () phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol ( 38a38a )의 제조Manufacturing
화합물 K- 2을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 38a 3 mg (62%)을 얻었다.Using Compound K- 2 , 3 mg (62%) of the title compound 38a was obtained by the same method as Step 5 of Example 1.
[실시예 107 내지 109][Examples 107 to 109]
상기 실시예 106의 방법을 이용하여 화합물 38b 내지 38d을 제조하였다. 제조된 화합물 38a 내지 38d의 동정자료를 하기 표 10에 기재하였다.Compounds 38b to 38d were prepared using the method of Example 106 above. Identification data of the prepared compounds 38a to 38d are shown in Table 10 below.
[표 10]TABLE 10
Figure PCTKR2016010369-appb-I000106
Figure PCTKR2016010369-appb-I000106
[실시예 110] (Z)-4-(1-(4-(2-(2,7-diazaspiro[4.4]nonan-2-yl)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (39)의 제조Example 110 (Z) -4- (1- (4- (2- (2,7-diazaspiro [4.4] nonan-2-yl) ethoxy) phenyl) -5-hydroxy-2-phenylpent-1- Preparation of en-1-yl) phenol ( 39 )
Figure PCTKR2016010369-appb-I000107
Figure PCTKR2016010369-appb-I000107
화합물 Q을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 39 0.8 mg (24%)을 얻었다.0.8 mg (24%) of the target compound 39 was obtained by the same method as Step 1 of Example 40, using compound Q.
1H-NMR(CD3OD, 400MHz) δ 7.18-7.07 (m, 5H), 7.0 (d, J = 7.0 Hz, 2H), 6.83 (d, J = 7.2 Hz, 2H), 6.76 (d, J = 7.0 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.23 (s, 2H), 3.81 (m, 2H), 3.66 (m, 2H), 3.41 (m, 8H), 2.51 (m, 2H), 2.21 (m, 4H), 1.54 (m, 2H). MS (ESI) m/z: 499 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.18-7.07 (m, 5H), 7.0 (d, J = 7.0 Hz, 2H), 6.83 (d, J = 7.2 Hz, 2H), 6.76 (d, J = 7.0 Hz, 2H), 6.68 (d, J = 7.6 Hz, 2H), 4.23 (s, 2H), 3.81 (m, 2H), 3.66 (m, 2H), 3.41 (m, 8H), 2.51 (m , 2H), 2.21 (m, 4H), 1.54 (m, 2H). MS (ESI) m / z: 499 [M + H] + .
[실시예 111] 4-((Z)-1-(4-(2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (40)의 제조Example 111 4-((Z) -1- (4- (2-((3aR, 6aS) -hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl) ethoxy) phenyl) -5 Preparation of -hydroxy-2-phenylpent-1-en-1-yl) phenol ( 40 )
Figure PCTKR2016010369-appb-I000108
Figure PCTKR2016010369-appb-I000108
화합물 R을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 40 2 mg (19%)을 얻었다.Using compound R to obtain 2 mg (19%) of the target compound 40 in the same manner as in Step 1 of Example 40.
1H-NMR(CD3OD, 400MHz) δ 7.08-7.16 (m, 5H), 7.04 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 4.31 (m, 2H), 4.04 (m, 2H), 3.83(m, 1H), 3.68 (m, 3H), 3.36-3.49 (m, 8H), 2.55 (m, 2H), 1.57 (m, 2H). MS (ESI) m/z: 485 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.08-7.16 (m, 5H), 7.04 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 4.31 (m, 2H), 4.04 (m, 2H), 3.83 (m, 1H), 3.68 (m, 3H), 3.36-3.49 (m, 8H), 2.55 (m, 2H), 1.57 (m, 2H). MS (ESI) m / z: 485 [M + H] + .
[실시예 112] (Z)-4-(1-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (42a)의 제조Example 112 (Z) -4- (1- (4- (dimethyl ((4-methylpiperazin-1-yl) methyl) silyl) phenyl) -5-hydroxy-2-phenylpent-1-en-1- Preparation of yl) phenol ( 42a )
Figure PCTKR2016010369-appb-I000109
Figure PCTKR2016010369-appb-I000109
단계 1: methyl (Z)-5-(4-(Step 1: methyl (Z) -5- (4- ( dimethyl(dimethyl ( (4-(4- methylpiperazinmethylpiperazin -1-yl)methyl)silyl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (-1-yl) methyl) silyl) phenyl) -4-phenyl-5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( L-L- 22 )의)of 제조 Produce
화합물 L-1을 이용하여 상기 실시예 106의 단계 1과 동일한 방법으로 목적화합물 L-2 8 mg (34%)을 얻었다.Using compound L-1 to obtain 8 mg (34%) of the target compound L-2 in the same manner as in Step 1 of Example 106.
단계 2: (Z)-4-(1-(4-(Step 2: (Z) -4- (1- (4- ( dimethyl(dimethyl ( (4-(4- methylpiperazinmethylpiperazin -1-yl)methyl)silyl)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (-1-yl) methyl) silyl) phenyl) -5-hydroxy-2-phenylpent-1-en-1-yl) phenol ( 42a42a )의 제조Manufacturing
화합물 L- 2을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 42a 3 mg (44%)을 얻었다.Using compound L- 2 to obtain 3 mg (44%) of the target compound 42a in the same manner as in Step 5 of Example 1.
[실시예 113 내지 116][Examples 113 to 116]
상기 실시예 112의 방법을 이용하여 화합물 42b 내지 42e을 제조하였다. 제조된 화합물 42a 내지 42e의 동정자료를 하기 표 11에 기재하였다.Compounds 42b to 42e were prepared using the method of Example 112 above. Identification data of the prepared compounds 42a to 42e is shown in Table 11 below.
[표 11]TABLE 11
Figure PCTKR2016010369-appb-I000110
Figure PCTKR2016010369-appb-I000110
[실시예 117] (E)-N-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)-2-(piperidin-1-yl)acetamide (44)의 제조Example 117 (E) -N- (4- (5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) -2- (piperidin-1-yl Preparation of acetamide ( 44 )
Figure PCTKR2016010369-appb-I000111
Figure PCTKR2016010369-appb-I000111
단계 1: methyl (E)-4-phenyl-5-(4-(2-(Step 1: methyl (E) -4-phenyl-5- (4- (2- ( piperidinpiperidin -1--One- ylyl )) acetamidoacetamido )phenyl)-5-(4-(pivaloyloxy)phenyl)pent-4-enoate () phenyl) -5- (4- (pivaloyloxy) phenyl) pent-4-enoate ( M-2M-2 )의 제조Manufacturing
화합물 M-1을 이용하여 상기 실시예 106의 단계 1과 동일한 방법으로 목적화합물 M-2 7 mg (80%)을 얻었다.Using compound M-1 , 7 mg (80%) of the target compound M-2 was obtained by the same method as Step 1 of Example 106.
단계 2: (E)-N-(4-(5-Step 2: (E) -N- (4- (5- hydroxyhydroxy -1-(4--1- (4- hydroxyphenylhydroxyphenyl )-2-)-2- phenylpentphenylpent -1-en-1-yl)phenyl)-2-(piperidin-1-yl)acetamide (-1-en-1-yl) phenyl) -2- (piperidin-1-yl) acetamide ( 4444 )의 제조Manufacturing
화합물 M- 2을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 44 2 mg (28%)을 얻었다.Using a compound M- 2 in the same manner as in Step 5 of Example 1 2 mg (28%) of the title compound 44 was obtained.
1H-NMR(CD3OD, 400MHz) δ 7.25 (d, J = 7.8 Hz, 2H), 7.17-7.10 (m, 5H), 7.05 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.01 (s, 2H), 3.57 (m, 2H), 3.44 (t, J = 6.7 Hz, 2H), 3.05 (m, 2H), 2.55 (m, 2H), 1.90 (m, 6H), 1.56 (m, 2H). MS (ESI) m/z: 471 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.25 (d, J = 7.8 Hz, 2H), 7.17-7.10 (m, 5H), 7.05 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.01 (s, 2H), 3.57 (m, 2H), 3.44 (t, J = 6.7 Hz, 2H), 3.05 (m, 2H ), 2.55 (m, 2H), 1.90 (m, 6H), 1.56 (m, 2H). MS (ESI) m / z: 471 [M + H] + .
[실시예 118] (E)-4-(5-hydroxy-2-phenyl-1-(4-((2-(piperidin-1-yl)ethyl)amino)phenyl)pent-1-en-1-yl)phenol (45)의 제조Example 118 (E) -4- (5-hydroxy-2-phenyl-1- (4-((2- (piperidin-1-yl) ethyl) amino) phenyl) pent-1-en-1- Preparation of yl) phenol ( 45 )
Figure PCTKR2016010369-appb-I000112
Figure PCTKR2016010369-appb-I000112
테트라하이드로퓨란 (2 mL)에 화합물 44 (10 mg, 0.02 mmol)을 넣고 0 ℃로 온도를 낮춘 뒤 1M 리튬알루미늄하이드라이드 (0.051 mL, 0.05 mmol)을 첨가하였다. 60 ℃에서 12시간 동안 가열하였다. 반응액에 물과 에틸아세테이트를 추가로 부가하여 유기층을 추출하였다. 유기층을 무수 Na2SO4로 건조시켜 여과하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용하여 정제한 다음, 메탄올:디클로로메탄(1:1)에 녹이고 0 ℃로 온도를 낮춰 1M HCl 수용액을 천천히 가한 다음, 감압증류하여 목적화합물 45 0.5 mg (6%)을 얻었다.Compound 44 (10 mg, 0.02 mmol) was added to tetrahydrofuran (2 mL), and the temperature was lowered to 0 ° C., followed by addition of 1M lithium aluminum hydride (0.051 mL, 0.05 mmol). Heated at 60 ° C. for 12 h. Water and ethyl acetate were further added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. A residue was obtained by evaporating the solvent under reduced pressure purified using column chromatography, and then methanol: dichloromethane (1: 1) lowering the temperature to 0 ℃ by distillation was added to 1M HCl aqueous solution slowly and then, under reduced pressure the desired compound 45 was dissolved in 0.5 mg (6%) was obtained.
1H-NMR(CD3OD, 400MHz) δ 7.15-7.07 (m, 5H), 7.01 (d, J = 8.4 Hz, 2H), 6.74 (m, 4H), 6.50 (d, J = 8.4 Hz, 2H), 3.61 (m, 2H), 3.48 (m, 2H), 3.40 (m, 6H), 2.51 (m, 2H), 1.81 (m, 4H), 1.55 (m, 4H). MS (ESI) m/z: 457 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.15-7.07 (m, 5H), 7.01 (d, J = 8.4 Hz, 2H), 6.74 (m, 4H), 6.50 (d, J = 8.4 Hz, 2H ), 3.61 (m, 2H), 3.48 (m, 2H), 3.40 (m, 6H), 2.51 (m, 2H), 1.81 (m, 4H), 1.55 (m, 4H). MS (ESI) m / z: 457 [M + H] + .
[실시예 119] 2-((3aR,6aS)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)acetamide (46)의 제조Example 119 2-((3aR, 6aS) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl) -N- (4-((E) -5-hydroxy- Preparation of 1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) acetamide ( 46 )
Figure PCTKR2016010369-appb-I000113
Figure PCTKR2016010369-appb-I000113
단계 1: Step 1: terttert -butyl (3aR,6aS)-5-(2-((4-((E)-5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (-butyl (3aR, 6aS) -5- (2-((4-((E) -5-methoxy-5-oxo-2-phenyl-1- (4- (pivaloyloxy) phenyl) pent-1-en- 1-yl) phenyl) amino) -2-oxoethyl) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate ( N-1N-1 )의 제조Manufacturing
화합물 M-1을 이용하여 상기 실시예 106의 단계 1과 동일한 방법으로 목적화합물 N-1 11 mg (99%)을 얻었다.Using compound M-1 , 11 mg (99%) of the target compound N-1 were obtained by the same method as Step 1 of Example 106.
단계 2: Step 2: terttert -butyl (3aR,6aS)-5-(2-((4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (-butyl (3aR, 6aS) -5- (2-((4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) amino) -2-oxoethyl) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate ( N-2N-2 )의 제조Manufacturing
화합물 N-1을 이용하여 상기 실시예 1의 단계 5와 동일한 방법으로 목적화합물 N-2 4 mg (39%)을 얻었다.Using compound N-1 to obtain 4 mg (39%) of the target compound N-2 in the same manner as in Step 5 of Example 1.
단계 3: 2-((3aR,6aS)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)acetamide (Step 3: 2-((3aR, 6aS) -3a, 6a-dimethylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl) -N- (4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) acetamide ( 4646 )의 제조Manufacturing
화합물 N- 2을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 46 1 mg (38%)을 얻었다.Using compound N- 2 , 1 mg (38%) of the target compound 46 was obtained by the same method as Step 1 of Example 40.
1H-NMR(CD3OD, 400MHz) δ 7.23 (d, J = 8.4 Hz, 2H), 7.17-7.08 (m, 5H), 7.03 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.24 (s, 2H), 3.43 (m, 8H), 2.52 (m, 2H), 1.52 (m, 4H). MS (ESI) m/z: 498 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.23 (d, J = 8.4 Hz, 2H), 7.17-7.08 (m, 5H), 7.03 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.24 (s, 2H), 3.43 (m, 8H), 2.52 (m, 2H), 1.52 (m, 4H). MS (ESI) m / z: 498 [M + H] + .
[실시예 120] (Z)-1-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent-1-en-1-yl)phenyl)guanidine (50)의 제조Example 120 (Z) -1- (4- (5-hydroxy-1- (4- (4-isopropylpiperazin-1-yl) phenyl) -2-phenylpent-1-en-1-yl) phenyl) Preparation of guanidine ( 50 )
Figure PCTKR2016010369-appb-I000114
Figure PCTKR2016010369-appb-I000114
단계 1: (Z)-5-(4-Step 1: (Z) -5- (4- aminophenylaminophenyl )-5-(4-(4-) -5- (4- (4- isopropylpiperazinisopropylpiperazin -1--One- ylyl )phenyl)-4-phenylpent-4-en-1-ol () phenyl) -4-phenylpent-4-en-1-ol ( O-O- 1One )의)of 제조 Produce
디메틸포름아마이드 (1 mL)에 화합물 26b (5 mg, 11 μmol), N,N'-다이-박-싸이오유레아 (3 mg, 0.01 mmol), 머큐리(II)클로라이드 (3 mg, 0.01 mmol), 트리에틸아민 (5 μL, 0.03 mmol)을 넣고 상온에서 12시간 동안 가열하였다. 용매를 감압 증류하여 얻은 잔사를 컬럼 크로마토그래피법을 이용, 정제하여 목적화합물 O- 1 6 mg (84%)을 얻었다.Dimethylformamide (1 mL) in compound 26b (5 mg, 11 μmol), N, N'-di-bac-thiourea (3 mg, 0.01 mmol), mercury (II) chloride (3 mg, 0.01 mmol) Triethylamine (5 μL, 0.03 mmol) was added and heated at room temperature for 12 hours. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography to obtain 6 mg (84%) of the title compound O- 1 .
단계 2: (Z)-1-(4-(5-Step 2: (Z) -1- (4- (5- hydroxyhydroxy -1-(4-(4--1- (4- (4- isopropylpiperazinisopropylpiperazin -1--One- ylyl )phenyl)-2-phenylpent-1-en-1-yl)phenyl)guanidine () phenyl) -2-phenylpent-1-en-1-yl) phenyl) guanidine ( 5050 )의)of 제조 Produce
화합물 O-1을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 50 0.5 mg (9%)을 얻었다. 50 mg (9%) of the title compound was obtained by the same method as Step 1 of Example 40 using compound O-1 .
MS (ESI) m/z: 498 [M+H]+.MS (ESI) m / z: 498 [M + H] + .
[실시예 121] (E)-4-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)piperazine-1-carboximidamide (52)의 제조Example 121 of (E) -4- (4- (5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) piperazine-1-carboximidamide ( 52 ) Produce
Figure PCTKR2016010369-appb-I000115
Figure PCTKR2016010369-appb-I000115
단계 1: Step 1: terttert -butyl ((E)-((tert-butoxycarbonyl)imino)(4-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)piperazin-1-yl)methyl)carbamate (-butyl ((E)-((tert-butoxycarbonyl) imino) (4- (4-((E) -5-hydroxy-1- (4-hydroxyphenyl) -2-phenylpent-1-en-1-yl) phenyl) piperazin-1-yl) methyl) carbamate ( P-1P-1 )의 제조Manufacturing
화합물 20c을 이용하여 상기 실시예 120의 단계 1과 동일한 방법으로 목적화합물 P-1 5 mg (36%)을 얻었다.5 mg (36%) of the title compound P-1 was obtained by the same method as Step 1 of Example 120 using compound 20c .
단계 2: (E)-4-(4-(5-Step 2: (E) -4- (4- (5- hydroxyhydroxy -1-(4--1- (4- hydroxyphenylhydroxyphenyl )-2-)-2- phenylpentphenylpent -1-en-1-yl)phenyl)piperazine-1-carboximidamide (-1-en-1-yl) phenyl) piperazine-1-carboximidamide ( 5252 )의 제조Manufacturing
화합물 P-1을 이용하여 상기 실시예 40의 단계 1과 동일한 방법으로 목적화합물 52 0.7 mg (23%)을 얻었다.Compound P-1 was used to obtain 0.7 mg (23%) of the title compound 52 in the same manner as in Step 1 of Example 40.
1H-NMR(CD3OD, 400MHz) δ 7.16-7.07 (m, 5H), 7.01 (m, 2H), 6.78 (m, 2H), 6.67 (m, 2H), 6.40 (d, J = 8.6 Hz, 2H), 3.67 (m, 2H), 3.28 (m, 2H), 3.48 (m, 1H), 3.41 (t, J = 6.7 Hz, 2H), 3.19 (m, 2H), 3.13 (m, 1H), 2.51 (m, 2H), 1.54 (m, 2H). MS (ESI) m/z: 457 [M+H]+. 1 H-NMR (CD 3 OD, 400 MHz) δ 7.16-7.07 (m, 5H), 7.01 (m, 2H), 6.78 (m, 2H), 6.67 (m, 2H), 6.40 (d, J = 8.6 Hz , 2H), 3.67 (m, 2H), 3.28 (m, 2H), 3.48 (m, 1H), 3.41 (t, J = 6.7 Hz, 2H), 3.19 (m, 2H), 3.13 (m, 1H) , 2.51 (m, 2H), 1.54 (m, 2H). MS (ESI) m / z: 457 [M + H] + .
[실험예 1] ERRγ, ERRα, ERRβ, ERα 결합 분석법(binding assay)Experimental Example 1 ERRγ, ERRα, ERRβ, ERα Binding Assay
1) ERRγ 결합 분석법 (inverse agonist assay)1) ERRγ binding assay (inverse agonist assay)
본 발명의 아릴에텐 유도체를 최종농도가 10μM부터 시작해서, 농도가 2배수로 희석되도록 순차적으로 384 well plate에 넣어주었다. 그리고, GST가 결합된 ERR gamma LBD (ligand-binding domain)를 최종농도 5nM이 되도록 첨가해 주고, fluorescien-conjugated coacitivator PGC1a와 Tb-a-GST antibody가 각각 500nM과 5nM이 되도록 첨가해 주었다. 모든 reagents가 첨가된 후, 20 ℃에서 1시간 동안 gently shaking을 해 주면서 반응시키고, 반응 후 binding activity는 TR-FRET 방식으로 측정하였다. 즉, 340nm에서 excitation 시키고, 495nm와 520nm에서 각각 emission 값을 측정한 후, 결과 분석은 490nm 측정값/520nm측정값으로 하였으며 분석프로그램은 Prism 6를 사용하였다. The arylethene derivative of the present invention was sequentially added to a 384 well plate so that the concentration was diluted by 2 times, starting with a final concentration of 10 μM. The GST-coupled ERR gamma LBD (ligand-binding domain) was added to a final concentration of 5 nM, and the fluorescien-conjugated coacitivators PGC1a and Tb-a-GST antibodies were added to 500 nM and 5 nM, respectively. After all the reagents were added, the reaction was gently shaken at 20 ° C. for 1 hour. After the reaction, binding activity was measured by TR-FRET method. That is, after excitation at 340nm, the emission value was measured at 495nm and 520nm, respectively, the result analysis was 490nm measurement value / 520nm measurement value, and the analysis program used Prism 6.
2) 2) ERRαERRα /  Of ERRβERRβ /  Of ERαERα 결합 분석법 (Selectivity test) Selectivity test
ERR alpha binding assay는 GST가 결합된 ERR alpha LBD를 사용하였으며, 그 이외의 모든 실험방법은 ERR gamma binding assay와 동일하였다. The ERR alpha binding assay used ERR alpha LBD combined with GST. All other methods were the same as the ERR gamma binding assay.
ERR beta binding assay는 GST가 결합된 ERR alpha LBD를 최종농도 10nM, fluorescien-conjugated coacitivator PGC1a는 250nM이 되도록 사용하였으며, 그 이외의 모든 실험방법은 ERR gamma binding assay와 동일하였다.In the ERR beta binding assay, GST-coupled ERR alpha LBD was used at a final concentration of 10 nM and the fluorescien-conjugated coacitivator PGC1a was 250 nM. All other experimental methods were the same as the ERR gamma binding assay.
ER alpha binding assay는 본 발명의 아릴에텐 유도체가 첨가된 384 well plate에 GST가 결합된 ER alpha LBD (ligand-binding domain)를 최종농도 7.3nM이 되도록 첨가해 주었다. 그리고, fluorescien-conjugated coacitivator PGC1a와 Tb-a-GST antibody가 각각 250nM과 5nM, agonist인 beta-estradiol을 최종농도 4nM이 되도록 첨가해 주었다. 이후의 모든 실험방법은 ERR gamma binding assay와 동일하였다.In the ER alpha binding assay, GST-coupled ER alpha LBD (ligand-binding domain) was added to a 384 well plate to which the arylethene derivative of the present invention was added to a final concentration of 7.3 nM. In addition, fluorescien-conjugated coacitivator PGC1a and Tb-a-GST antibodies were added to 250nM, 5nM, and agonist beta-estradiol to a final concentration of 4nM. All subsequent experiments were identical to the ERR gamma binding assay.
상기 실험예 1의 결과를 하기 표 12에 나타내었다.The results of Experimental Example 1 are shown in Table 12 below.
[표 12]TABLE 12
Figure PCTKR2016010369-appb-I000116
Figure PCTKR2016010369-appb-I000116
Figure PCTKR2016010369-appb-I000117
Figure PCTKR2016010369-appb-I000117
[[ 실험예Experimental Example 2]  2] ERRγERRγ 역작동제Inverse 기능 분석법 (inverse  Function analysis (inverse agonistagonist functional assay) functional assay)
AD293을 9 X 104개/well 농도로 0.5% FBS를 첨가한 DMEM High glucose (Hyclone, USA) 배양액을 사용하여 24 well plate에서 24시간 배양하였다. 10% FBS를 첨가한 DMEM High glucose 배양액으로 교체하고, TransIT-LT1 transfection reagent (Mirus, USA)와 pCMX-Gal4-ERRγ, pFR-luciferase reporter plasmid, pCMV-β-gal을 섞어 함께 처리한 후 24시간 배양하였다. 이후 본 발명의 아릴에텐 유도체를 24시간 처리한 뒤 얻은 lysate로 luciferase activity assay와 β-gal assay를 각각 수행하였다. 모든 결과는 세 번 이상의 독립되고 반복된 실험으로부터 도출하였다. AD293 was incubated in a 24 well plate for 24 hours using DMEM High glucose (Hyclone, USA) culture with 0.5% FBS at 9 × 10 4 / well. Replace with DMEM High glucose culture medium with 10% FBS, mix with Trans IT-LT1 transfection reagent (Mirus, USA), pCMX-Gal4-ERRγ, pFR-luciferase reporter plasmid, and pCMV-β-gal. Time incubation. Then, luciferase activity assay and β-gal assay were performed with lysate obtained after 24 hours of arylethene derivative of the present invention. All results were derived from three or more independent and repeated experiments.
그 결과를 하기 표 13에 기재하였으며, "Cpds"는 화합물을 처리하였을 때 inverse agonist functional 활성을 의미하며, "Ref 5182"는 에세이 할 때마다 데이터 검증을 위한 레퍼런스 화합물 GSK5182의 활성을 의미하며, "Cpds/Ref 5182"는 레퍼런스화합물 대비 본 발명의 아릴에텐 유도체의 활성 정도를 의미한다.The results are shown in Table 13 below, "Cpds" refers to inverse agonist functional activity when the compound is treated, and "Ref 5182" refers to the activity of the reference compound GSK5182 for data validation every time the assay is performed. Cpds / Ref 5182 "refers to the degree of activity of the arylethene derivative of the present invention relative to the reference compound.
[표 13]TABLE 13
Figure PCTKR2016010369-appb-I000118
Figure PCTKR2016010369-appb-I000118
Figure PCTKR2016010369-appb-I000119
Figure PCTKR2016010369-appb-I000119
Figure PCTKR2016010369-appb-I000120
Figure PCTKR2016010369-appb-I000120
[[ 실험예Experimental Example 3] 생체 외(in vitro)  3] in vitro ADMEADME /Of ToxTox (absorption, distribution, metabolism, excretion, and toxicity) 평가 (absorption, distribution, metabolism, excretion, and toxicity)
1) One) CYP450CYP450 (( cytochromecytochrome P450) 활성 억제 평가 P450) activity inhibition assessment
Human liver microsomes (0.25 mg/ml)과 0.1M 인산 완충용액 (pH 7.4), 5종의 약물대사효소의 기질 약물 칵테일 (Phenacetin 50 μM, Diclofenac 10 μM, S-mephenytoin 100 μM, Dextromethorphan 5 μM, Midazolam 2.5 μM) 및 본 발명의 아릴에텐 유도체를 각각 0, 10 μM 농도로 첨가하고, 37 ℃에서 5분간 미리 배양한 후, NADPH generation system 용액을 첨가하고 37 ℃에서 15분간 배양하였다. 이후 반응을 종결시키기 위해 내부표준물질(Terfenadine)이 포함된 아세토니트릴 용액을 첨가하고, 5분간 원심분리(14,000 rpm, 4 ℃) 한 후 상층액을 LC-MS/MS 시스템에 주입하여 기질약물의 대사물을 동시에 분석함으로써 본 발명의 아릴에텐 유도체에 의한 약물대사효소 저해능을 평가하였다.Human liver microsomes (0.25 mg / ml) and 0.1M phosphate buffer (pH 7.4), substrate drug cocktails of 5 drug metabolic enzymes (Phenacetin 50 μM, Diclofenac 10 μM, S-mephenytoin 100 μM, Dextromethorphan 5 μM, Midazolam 2.5 μM) and arylethene derivatives of the present invention were added at concentrations of 0 and 10 μM, respectively, and pre-incubated at 37 ° C. for 5 minutes, followed by the addition of a NADPH generation system solution and incubation at 37 ° C. for 15 minutes. Then, to terminate the reaction, acetonitrile solution containing internal standard (Terfenadine) was added, centrifuged for 5 minutes (14,000 rpm, 4 ° C), and the supernatant was injected into the LC-MS / MS system. Simultaneous analysis of the metabolites evaluated the drug metabolism inhibitory ability by the arylethene derivatives of the present invention.
그 결과를 하기 표 14에 기재하였다.The results are shown in Table 14 below.
[표 14]TABLE 14
Figure PCTKR2016010369-appb-I000121
Figure PCTKR2016010369-appb-I000121
Figure PCTKR2016010369-appb-I000122
Figure PCTKR2016010369-appb-I000122
2) 2) MicrosomalMicrosomal Stability 평가 Stability evaluation
4종의 liver microsomes (Human, Dog, Rat, Mouse 0.5 mg/ml)과 0.1M 인산 완충용액 (pH 7.4), 본 발명의 아릴에텐 유도체를 1 μM 농도로 첨가하고 37 ℃에서 5분간 미리 배양한 후, NADPH Regeneration system 용액을 첨가하여 37 ℃에서 30분간 배양하였다. 이후 반응을 종결시키기 위해 내부표준물질(chlorpropamide)이 포함된 아세토니트릴 용액을 첨가하고, 5분간 원심분리(14,000 rpm, 4 ℃) 한 후 상층액을 LC-MS/MS 시스템에 주입하여 기질약물을 분석함으로써 본 발명의 아릴에텐 유도체에 대한 대사안정성을 평가하였다. Four liver microsomes (Human, Dog, Rat, Mouse 0.5 mg / ml), 0.1 M phosphate buffer (pH 7.4) and arylethene derivatives of the present invention were added at a concentration of 1 μM and pre-incubated at 37 ° C. for 5 minutes. After that, the NADPH Regeneration system solution was added and incubated at 37 ° C. for 30 minutes. Then, to terminate the reaction, acetonitrile solution containing chlorpropamide was added, centrifuged for 5 minutes (14,000 rpm, 4 ° C.), and the supernatant was injected into the LC-MS / MS system. By analyzing, the metabolic stability of the arylethene derivative of the present invention was evaluated.
그 결과를 하기 표 15에 기재하였다.The results are shown in Table 15 below.
[표 15]TABLE 15
Figure PCTKR2016010369-appb-I000123
Figure PCTKR2016010369-appb-I000123
Figure PCTKR2016010369-appb-I000124
Figure PCTKR2016010369-appb-I000124
3) PAMPA(parallel artificial membrane permeability assay) 평가 3) PAMPA (parallel artificial membrane permeability assay) evaluation
PAMPA는 물질의 세포막 투과도를 시험관에서 테스트하기 위해 개발된 방법으로써, cornig gentest사 (NY, US)의 lipid tri-layer PVDF membrane을 사용해서 수행되었고, 사용된 시약들은 모두 Sigma (MO, US)사에서 구입하였다. 먼저, 테스트 물질을 PBS (pH7.4)에 최종농도가 10 mM이 되도록 희석한 후, 300 mL를 PVDF membrane이 장착된 96 transwell의 bottom well에 첨가하고, PBS 200 mL를 upper well에 첨가해 준다. 그리고, plate를 5시간동안 25 ℃에서 반응시킨 후, 각 well에서 20 mL의 용액을 새로운 용기에 옮긴 후, 내부표준물질 (4mM chloropropamide)이 포함된 acetonitrile 80 mL를 첨가한다. 용액내 물질의 농도는 LC-MS/MS (ThermoFisher Scientific, MO, US)를 이용해 분석하고, 물질의 투과도는 참고문헌에 보고된 식에 따라 계산한다. PAMPA was developed to test cell membrane permeability of a substance in vitro, and was performed using lipid tri-layer PVDF membrane of cornig gentest (NY, US). All reagents used were Sigma (MO, US). Purchased from First, dilute the test substance to a final concentration of 10 mM in PBS (pH7.4), add 300 mL to the bottom well of a 96 transwell equipped with PVDF membrane, and add 200 mL of PBS to the upper well. . After the plate is reacted at 25 ° C. for 5 hours, transfer 20 mL of solution from each well to a new container, and add 80 mL of acetonitrile containing 4 mM chloropropamide. The concentration of material in solution is analyzed using LC-MS / MS (ThermoFisher Scientific, MO, US), and the permeability of the material is calculated according to the formula reported in the reference.
참고문헌 : A Novel Design of artificial membrane for improving the PAMPA model. Chen X, Murawski A, et al. Pharmaceutical Research. 25:1511, 2007References: A Novel Design of artificial membrane for improving the PAMPA model. Chen X, Murawski A, et al. Pharmaceutical Research. 25: 1511, 2007
그 결과를 하기 표 16에 기재하였다.The results are shown in Table 16 below.
[표 16]TABLE 16
Figure PCTKR2016010369-appb-I000125
Figure PCTKR2016010369-appb-I000125
4) 4) hERGhERG channel 결합  channel bonding 저해능Inhibition 평가 evaluation
Positive Control 로서 E-4031 (유효 IC50: 10-90nM) 화합물을 3-fold로 단계적으로 희석시킨 후 미리 준비된 hERG channel이 함유된 membrane과 형광성 tracer와 함께 mix하여 4시간 반응시킨 뒤 농도별 polarization값을 측정하여 IC50을 얻었다. 본 발명의 아릴에텐 유도체에 대하여, 단계적으로 희석된 16 points 농도에서의 Fluorescence Intensity (Excitation at 530nm, Emission at 590nm)를 측정하여 DMSO 용매 control과 비교였다.As a positive control, E-4031 (Effective IC50: 10-90nM) compound was diluted in 3-fold stepwise, mixed with membrane prepared with hERG channel and fluorescent tracer and reacted for 4 hours. measured to obtain the IC 50. For the arylethene derivatives of the present invention, Fluorescence Intensity (Excitation at 530nm, Emission at 590nm) at 16 point concentrations diluted in stages was measured and compared with DMSO solvent control.
hERG Fluorescence Polarization Assay (Invitrogen: PV5365) kit을 사용하였다.hERG Fluorescence Polarization Assay (Invitrogen: PV5365) kit was used.
그 결과를 하기 표 17에 기재하였다.The results are shown in Table 17 below.
[표 17]TABLE 17
Figure PCTKR2016010369-appb-I000126
Figure PCTKR2016010369-appb-I000126
[[ 실험예Experimental Example 4] 생체 내 약물동태(in  4] in vivo pharmacokinetics (in vivovivo PK) 평가 PK) evaluation
본 발명의 화합물을 랫(rat)에 정맥 또는 경구투여하였을 때 약물동태학적 거동을 알아보기 위하여 최소 200g의 랫을 사용하여 다음과 같은 실험을 실시하였으며, 그 결과를 하기 표 18에 나타내었다.In order to determine the pharmacokinetic behavior when the compound of the present invention was administered intravenously or orally to rats, the following experiment was conducted using at least 200 g of rats, and the results are shown in Table 18 below.
가. 실험방법end. Experiment method
1. 경구투여군에 대해 하루전에 절식을 시킨다1. Fast the day before oral administration group
2. 각 동물의 시간 0 혈액을 채취한다2. Collect blood for each animal at time 0
3. 정맥투여군(IV)에 꼬리정맥으로 1mg/kg 용량으로 약물을 투입한다 (주사기).3. In the IV group (IV), the drug is injected into the tail vein at a dose of 1 mg / kg (syringe).
4. 경구투여군(PO)에게 경구로 10mg/kg 용량으로 약물을 투입한다 (경구용 zondec).4. Oral administration (PO) to the drug orally (10 mg / kg) (oral zondec).
5. 투여 후 정맥투여 군의 경우 0.08, 0.25, 0.5, 1, 2, 4, 6, 8시간 동안 8번의 채혈을 경정맥에서 실시한다. 1회 채혈량은 400~500ul이다.5. In the intravenous group after administration, eight blood collections are performed in the jugular vein for 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 hours. The volume of blood drawn is 400 ~ 500ul.
6. 투여 후 경구투여군의 경우 0.25, 0.5, 1, 4, 6, 8시간 동안 6번의 채혈을 경정맥에서 실시한다. 1회 채혈량은 400~500ul이다.6. After oral administration, six blood samples are taken from the jugular vein for 0.25, 0.5, 1, 4, 6 and 8 hours. The volume of blood drawn is 400 ~ 500ul.
7. 각 혈액을 3.8% sodium citrate용액과 섞어 얼음에 보관한다.7. Mix each blood with 3.8% sodium citrate solution and store on ice.
8. 원심분리기를 통해서 상등액 plasma를 모은다.8. Collect the supernatant plasma through a centrifuge.
9. LC-MS/MS 시스템에 주입하여 약물을 분석한다.9. Analyze drug by injection into LC-MS / MS system.
[표 18]TABLE 18
Figure PCTKR2016010369-appb-I000127
Figure PCTKR2016010369-appb-I000127
[[ 실험예Experimental Example 5] 미분화  5] Undifferentiated 감상선암에On adenocarcinoma 대한 실험  For experiment
1. 재료 및 방법1. Materials and Methods
1.1. 세포1.1. cell
미분화 갑상선암 세포주인, CAL-62를 Deutsche Sammlung von Mikroorganismen und Zellkulturen로부터 구매하였다. 세포주를 모두 10% FBS, 1% 항생제-항진균제 (Hyclone)로 고도로 보충된 DMEM 배지 내에서, 5% CO2 분위기하에서 37℃로 유지하였다. Enhanced firefly luciferase 유전자(effluc)가 발현하는 레트로 바이러스를 CAL-62세포에 처리하여 effluc 유전자가 안정하게 발현하는 세포주를 확립하였다. 이렇게 확립된 세포주를 CAL-62/effluc 세포라 명명하였다.CAL-62, an undifferentiated thyroid cancer cell line, was purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen. Cell lines were all maintained at 37 ° C. under 5% CO 2 atmosphere in DMEM medium, highly supplemented with 10% FBS, 1% antibiotic-antifungal (Hyclone). Retroviruses expressing the enhanced firefly luciferase gene (effluc) were treated with CAL-62 cells to establish a cell line stably expressing the effluc gene. This established cell line was named CAL-62 / effluc cells.
1.2. 125I 섭취 분석 (Uptake Assay)1.2. 125 I Uptake Assay
세포들을 24-웰 플레이트에 24시간 동안 플레이팅한 후, 화합물 18a로 처리하고, DMSO 중 100mM 저장(stock) 용액으로 제조하고 -80℃에서 24시간 동안 저장하였다. 약물-함유 배지를 흡인 후, 세포를 1mL HBSS로 세척하고, 0.5% 소 혈청 알부민 (bHBSS), 3.7kBq 무-담체(carrier-free) 125I (Perkin-Elmer) 및 10μmol/L의 요오드화 나트륨 (비활성 740MBq/mmol)을 함유하는 행크스 균형 염용액 (Hank' balanced salt solution: HBSS) 500μ와 함께 37℃에서 30분 동안 인큐베이션하였다. 그 후 세포들을 빙냉된 bHBSS로 2회 세척하고, 500μl의 2% 나트륨 도데실 설페이트 (SDS)로 용균시켰다. 감마 카운터 (Cobra II; Canberra Packard, Packard Bioscience)를 이용하여 방사능을 측정하였다. 세포들의 방사능을 BCA 키트 (Pierce Protein Biology)에 의해 결정된 총 단백질 농도를 이용하여 정규화하였다.Cells were plated in 24-well plates for 24 hours, then treated with Compound 18a, prepared as 100 mM stock solution in DMSO and stored at -80 ° C for 24 hours. After aspirating the drug-containing medium, the cells were washed with 1 mL HBSS, 0.5% bovine serum albumin (bHBSS), 3.7 kBq carrier-free 125 I (Perkin-Elmer) and 10 μmol / L sodium iodide ( Incubated at 37 ° C. for 30 minutes with 500 μl Hank 'balanced salt solution (HBSS) containing inactive 740 MBq / mmol). Cells were then washed twice with ice cold bHBSS and lysed with 500 μl of 2% sodium dodecyl sulfate (SDS). Radioactivity was measured using a gamma counter (Cobra II; Canberra Packard, Packard Bioscience). Radioactivity of cells was normalized using total protein concentration determined by BCA kit (Pierce Protein Biology).
1.3. 화합물 18a 약물 농도에 따른 125I 섭취 분석1.3. Analysis of 125 I Intake According to Compound 18a Drug Concentration
세포들을 다양한 농도의 (Vehicle, 6, 12uM) 화합물 18a로 처리한 후, 이어서 상기 기재된 것과 같이 125I 섭취 시험을 하였다.Cells were treated with various concentrations of (Vehicle, 6, 12 uM) Compound 18a followed by a 125 I uptake test as described above.
1.4. KClO4에 의한 125I 섭취 섭취 저해 분석1.4. Inhibition of 125 I Intake Intake by KClO 4
세포들을 300μM KClO4 (NIS에 대한 특이적 저해제로서)와 함께 30분 동안 예비-인큐베이션하여 요오드 섭취를 저해하고, 이어서 상기 기재된 것과 같이 125I 섭취 시험을 하였다.Cells were pre-incubated with 300 μM KClO 4 (as a specific inhibitor for NIS) for 30 minutes to inhibit iodine uptake, followed by a 125 I uptake test as described above.
1.5. MAK 카이나제 저해제에 의한 125I 섭취 섭취 저해 분석: 세포들을 PD98059 또는 U0126 (MAP kinase에 대한 특이적 저해제로서)와 함께 30분 동안 예비-인큐베이션하여 요오드 섭취를 저해하고, 이어서 상기 기재된 것과 같이 125I 섭취 시험을 하였다.1.5. Inhibition of 125 I Uptake Intake by MAK Kinase Inhibitors: Cells were pre-incubated with PD98059 or U0126 (as a specific inhibitor for MAP kinase) for 30 minutes to inhibit iodine uptake and then 125 as described above. I intake test was performed.
1.6 Quantitative RT-PCR1.6 Quantitative RT-PCR
Total RNA는 Trizol (Invitrogen, Carlsbad, CA)를 이용하여 분리하였다. Total RNA (2ug)을 RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, Pittsburgh, PA)로 cDNA로 역전사하였다. cDNA template를 이용하여 각 목적 유전자의 프라이머 (primer)와 YBR Green PCR master mix (Applied Biosystems, Foster City, CA)를 이용하여 ViiA 7 Real-Time PCR System instrument (Applied Biosystems)기계로 증폭시켰다. 각 목적 유전자의 프라이머 시퀀스는 다음과 같다; ERRγ (forward, 5'- CAG ACG CCA GTG GGA GCT A -3'; reverse, 5'- TGG CGA GTC AAG TCC GTT CT - 3'), NIS (forward, 5'- TCT AAC CGA TGC TCA CCT CTT CTG -3'; reverse, 5'- AGA TGA TGG CAC CTC CTT GAA CC -3'), and acidic ribosomal protein 36B4 (forward, 5'-CCA CGC TGC TGA ACA TGC T -3'; reverse, 5'- TCG AAC ACC TGC TGG ATG AC -3'). 각 목적 유전자는 36B4 유전자를 이용하여 정규화하였다. Total RNA was isolated using Trizol (Invitrogen, Carlsbad, CA). Total RNA (2ug) was reverse transcribed into cDNA with the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, Pittsburgh, Pa.). The cDNA template was used to amplify the primer of each target gene and YBR Green PCR master mix (Applied Biosystems, Foster City, CA) using a ViiA 7 Real-Time PCR System instrument (Applied Biosystems). The primer sequence of each target gene is as follows; ERRγ (forward, 5'- CAG ACG CCA GTG GGA GCT A -3 '; reverse, 5'- TGG CGA GTC AAG TCC GTT CT-3'), NIS (forward, 5'- TCT AAC CGA TGC TCA CCT CTT CTG -3 '; reverse, 5'- AGA TGA TGG CAC CTC CTT GAA CC -3'), and acidic ribosomal protein 36B4 (forward, 5'-CCA CGC TGC TGA ACA TGC T -3 '; reverse, 5'- TCG AAC ACC TGC TGG ATG AC -3 '). Each target gene was normalized using 36B4 gene.
1.7. 클론형성(Clonogenic) 분석1.7. Clonogenic Assay
세포들을 6-웰 플레이트에 도말하고, 24시간 동안 두었다. 12μM 화합물 18a를 이용하여 24시간 동안 처리 후, 약물-함유 배지를 폐기하고 세포를 PBS로 2회 세척하였다. 배지를 그 후 6시간 동안 50μCi 131I (KIRAMS, Korea) 존재 또는 부재 하에서 DMEM으로 대체하였다. 세포들을 차가운 bHBSS로 세척하고, 6회의 배가 (six doublings)에 대응하는 시간 동안 정규 배양 배지에 두었다. 최종적으로, 세포들을 4% 파라포름알데히드 (PFA) 용액 내에서 고정시키고 0.05% 크리스탈 바이올렛 (crystal violet)으로 염색하였다. 50개가 넘는 세포를 갖는 제어 콜로니 및 131I 처리된 콜로니를 계수하였다.Cells were plated in 6-well plates and left for 24 hours. After 24 hours of treatment with 12 μM compound 18a, the drug-containing medium was discarded and the cells washed twice with PBS. The medium was then replaced with DMEM in the presence or absence of 50 μCi 131 I (KIRAMS, Korea) for 6 hours. Cells were washed with cold bHBSS and placed in normal culture medium for a time corresponding to six doublings. Finally, cells were fixed in 4% paraformaldehyde (PFA) solution and stained with 0.05% crystal violet. Control colonies and 131 I treated colonies with more than 50 cells were counted.
1.8. 웨스턴 블롯1.8. Western Blot
세포들을 화합물 18a 없이 또는 화합물 18a와 함께 24 시간 동안 처리하고, 차가운 PBS로 2회 세척하였으며, 완전한 프로테아제 저해제 칵테일을 함유하는 RIPA 버퍼 (Roche)로 용균시켰다. NIS에 대한 세포막 단백질의 경우, 샘플들을 제조자 지시사항에 따라 단백질 비오티닐화 키트 (EZ-Link™ Sulfo-NHS-Biotin, Thermo Scientific)를 이용하여 제조하였다. 간략하게는, 비처리된-세포 또는 처리된 세포들 중 어느 하나를 빙냉된 PBS/CM (0.1mM 염화 칼슘 및 1mM 염화 마그네슘을 함유하는 PBS, pH 7.3)로 2회 세척하고, PBS/CM 중의 EZ 링크 NHS-설포-SS-비오틴 (1mg/mL)과 함께 4℃에서 30분 동안 인큐베이션하였다. 반응을 PBS/CM 중 차가운 100mM 글리신을 이용하여 2회 세척함으로써 퀀칭시키고, PBS/CM 중 100mM 글리신과 함께 4℃에서 20분 동안 추가로 인큐베이션하였다. 그 후 세포들을 4℃에서 1시간 동안 일정하게 진탕하며 프로테아제 저해제 칵테일 및 포스파타제 저해제를 함유하는 RIPA 버퍼 (Roche)를 이용하여 용균시키기 전에 PBS/CM을 이용하여 빠르게 2회 세척하였다. 용균액을 4℃에서 30분 동안, 16,000g에서 원심분리하였다. 상등액 일부는 총 세포 단백질 면역블롯에 대해 사용하였다. 잔여 샘플을, 실온에서 1시간 동안 100μL 스트렙트아비딘 비즈 (Thermo Scientific)와 함께 인큐베이션함으로써 막 단백질을 수득하는데 이용하였다. 비즈를 RIPA 버퍼를 이용하여 3회 세척하고, 결합된 단백질을 실온에서 30분 동안 50μL의 라에멜리(Laemmli) 버퍼 (62.5M 트리스, pH 6.8; 20% 글리세롤; 2% SDS; 5% b-머캡토에탄올; 및 0.01% 브롬페놀 블루)를 이용하여 용리하였다. 균등량의 총 세포막 단백질 및 비오티닐화 세포막 단백질을 각 레인(lane) 위에 부하하고(load) 4-12% 기울기 Bis-Tris 겔 (Invitrogen)에 의해 분해시켰다(resolve). 단백질을 0.2μm PVDF 막 (Invitrogen)으로 이동시켰다. 막을 일차 쥐 단일클론성 인간 NIS-특이적 항체 (희석 1:1000, Thermo Scientific, Catalog#: MS-1653-P1, 클론: FP5A)와 함께 인큐베이션하고, 이어서 HRP-공액된 2차 항체와 함께 실온에서 인큐베이션하였다. ECL-Plus (Amersham Pharmacia)는, 제조자 방법에 따라 퍼옥시다아제 활성을 검출하는데 사용되었다. 유사하게, 다른 단백질의 경우에서도, 단백질의 균등량을 각 레인에 부하하고, 4-12% 기울기 Bis-Tris 겔 (Invitrogen)에 의해 분해시켰다. 단백질을 0.2μm PVDF 막 (Invitrogen)으로 이동시켰다. 막을 일차 항체 (ERRγ, pERK1/2, β-actin) 와 함께 4℃에서 하룻밤 동안 인큐베이션하고, 그 후 실온에서 적절한 HRP-공액된 이차 항체와 함께 인큐베이션하였다. 제조자 프로토콜에 따라 ECL-Plus를 이용하여 퍼옥시다아제 활성을 검출하였다. 밴드 밀도를 ImageJ 소프트웨어를 이용하여 결정하였다.Cells were treated for 24 hours without or with compound 18a, washed twice with cold PBS and lysed with RIPA buffer (Roche) containing a complete protease inhibitor cocktail. For cell membrane proteins for NIS, samples were prepared using a protein biotinylation kit (EZ-Link ™ Sulfo-NHS-Biotin, Thermo Scientific) according to manufacturer's instructions. Briefly, either untreated-cells or treated cells were washed twice with ice-cold PBS / CM (PBS containing 0.1 mM calcium chloride and 1 mM magnesium chloride, pH 7.3) and in PBS / CM Incubate with EZ Link NHS-sulfo-SS-biotin (1 mg / mL) at 4 ° C. for 30 minutes. The reaction was quenched by washing twice with cold 100 mM glycine in PBS / CM and further incubated for 20 minutes at 4 ° C. with 100 mM glycine in PBS / CM. The cells were then washed twice quickly with PBS / CM before lysis using RIPA buffer (Roche) containing a protease inhibitor cocktail and a phosphatase inhibitor with constant shaking at 4 ° C. for 1 hour. The lysate was centrifuged at 16,000 g for 30 minutes at 4 ° C. Part of the supernatant was used for total cell protein immunoblot. The remaining sample was used to obtain membrane protein by incubating with 100 μL Streptavidin beads (Thermo Scientific) for 1 hour at room temperature. The beads were washed three times with RIPA buffer and the bound protein was washed with 50 μL of Laemmli buffer (62.5 M Tris, pH 6.8; 20% glycerol; 2% SDS; 5% b- for 30 minutes at room temperature). Mercaptoethanol; and 0.01% brominephenol blue). Equal amounts of total cell membrane protein and biotinylated cell membrane protein were loaded on each lane and resolved by 4-12% gradient Bis-Tris gel (Invitrogen). Protein was transferred to 0.2 μm PVDF membrane (Invitrogen). Membranes are incubated with primary murine monoclonal human NIS-specific antibody (dilution 1: 1000, Thermo Scientific, Catalog #: MS-1653-P1, clone: FP5A), followed by room temperature with HRP-conjugated secondary antibody Incubated at. ECL-Plus (Amersham Pharmacia) was used to detect peroxidase activity according to the manufacturer's method. Similarly, for other proteins, an equivalent amount of protein was loaded in each lane and digested by 4-12% gradient Bis-Tris gel (Invitrogen). Protein was transferred to 0.2 μm PVDF membrane (Invitrogen). Membranes were incubated with primary antibodies (ERRγ, pERK1 / 2, β-actin) overnight at 4 ° C. and then incubated with appropriate HRP-conjugated secondary antibodies at room temperature. Peroxidase activity was detected using ECL-Plus according to the manufacturer's protocol. Band density was determined using ImageJ software.
1.9. 동물실험1.9. Animal testing
Nude 마우스 (Balb/c nu/nu, 암컷, 6주령)을 사용하였고, 모든 동물은 칠곡경북대학교병원 DMRC 센터 동물 실험실에서 정상적으로 사육하였다. 5x106 CAL-62/effluc 세포를 nude 마우스 좌측 대퇴부에 피하주사하여 종양형성을 시켰다. 종양을 적출하여 작은 사이즈 (20mg 이상)로 조각을 낸 후 다시 nude 마우스에 피내주사하여 종양형성을 시켰다.Nude mice (Balb / c nu / nu, female, 6 weeks old) were used and all animals were bred normally in the animal laboratory at Chilgok Kyungpook National University Hospital DMRC Center. Tumor formation was performed by subcutaneous injection of 5 × 10 6 CAL-62 / effluc cells into the left thigh of nude mice. Tumors were extracted, sliced into small size (20 mg or more), and injected again into nude mice for tumor formation.
종양형성 후 CAL-62/effluc 마우스 종양모델을 다음과 같이 그룹을 나눴다; 그룹 1: Vehicle, 그룹 2: 100mpk 화합물 18a, 그룹 3: 200mpk 화합물 18a. 각 그룹의 마우스에게 매일 vehicle (100% PEG), 화합물 18a (100mpk, 200 mpk)를 6일 동안 경구투여 하였다. 투여전과 투여 후 종양성장차이를 관찰하기 위하여 광학영상을 (bioluminescent imaging)을 수행하였다. 약물 투여하는 동안 마우스 체중변화를 이틀에 한번씩 관찰하였다.After tumor formation, the CAL-62 / effluc mouse tumor model was divided into the following groups; Group 1: vehicle, group 2: 100 mpk compound 18a, group 3: 200 mpk compound 18a. Mice in each group were orally administered vehicle (100% PEG) and compound 18a (100 mpk, 200 mpk) daily for 6 days. Bioluminescent imaging was performed to observe tumor growth differences before and after administration. Mouse weight changes were observed every other day during drug administration.
또한 CAL-62/effluc 종양 내에 125I 섭취의 증가변화를 확인하기 위하여 장기분포조사(Bio-distribution study)를 다음과 같이 수행하였다. 약물 마지막 투여 후 다음 날 마우스에 125I (5uCi/mouse)를 정맥주사를 통하여 투여하였다. 투여 후 4시간 후에 모종양을 포함 모든 장기들을 적출하고 각 장기들의 무게를 측정하였다. 그 후 각 장기들을 5ml 테스트 튜브에 옮긴 후 감마카운트(gamma counter)를 이용하여 장기 내 방사능(radioactivity)을 측정하였다. 장기내 125I 섭취 정도는 percentage injected dose per gram (%ID/g)으로 표현하였다.In addition, a bio-distribution study was performed to confirm the change in 125 I intake in CAL-62 / effluc tumors. The next day after the last drug administration, mice were administered 125 I (5 uCi / mouse) intravenously. Four hours after administration, all organs, including the parent tumor, were removed and each organ was weighed. Each organ was then transferred to a 5 ml test tube and then radioactivity was measured using a gamma counter. The intake of 125 I in organs was expressed as percentage injected dose per gram (% ID / g).
1.10. 동물영상1.10. Animal
광학영상을 얻기 위하여 마우스에 D-luciferin (3mg/mouse)을 복강주사하였다. 주사 후 약 10분 후 마우스를 흡입마취를 (1-2% isoflurane gas) 시킨 후 IVIS Lumina III (PerkinElmer) 영상베드에 위치 시켰다. 영상획득 시간은 자동으로 설정 후 광학영상을 획득하였다. Living imaging software (version 2.12, PerkinElmer)를 이용하여 종양에서 나오는 광학영상 신호를 정량하였다.To obtain optical images, mice were intraperitoneally injected with D-luciferin (3 mg / mouse). About 10 minutes after injection, mice were inhaled with anesthesia (1-2% isoflurane gas) and placed on an IVIS Lumina III (PerkinElmer) imaging bed. The image acquisition time was automatically set, and then the optical image was acquired. Optical imaging signals from tumors were quantified using Living imaging software (version 2.12, PerkinElmer).
1.11. 통계 분석1.11. Statistical analysis
모든 데이터는 평균±로서 나타내었으며, 통계적 유의성은 GraphPad Prism 5의 스튜던트 검정(Studenttest)을 이용하여 결정하였다. P 값 < 0.05를 통계적으로 유의한 것으로 간주하였다.All data are expressed as mean ± and statistical significance was determined using Student's test of GraphPad Prism 5. P values <0.05 were considered statistically significant.
2. 결과2. Results
2.1 화합물 18a에 의한 ATC 세포에서의 증진된 방사성요오드 섭취2.1 Enhanced Radioiodine Intake in ATC Cells by Compound 18a
화합물 18a 처리 후 농도와 시간 별에 따라 CAL62 세포에서 방사성 요오드 섭취의 현저한 증가를 확인 할 수 있었다(도 1 및 도 2). 요오드 섭취 최대 증가는 12uM 화합물 18a의 농도에서 관찰되었다. 증가된 방사성 요오드 섭취가 화합물 18a에 의하여 NIS 작용의 조절에 관련되는지의 여부를 시험하기 위하여, NIS 의 특이적 저해제인 KClO4를 화합물 18a-처리된 CAL62 세포와 함께 공동 인큐베이션하고, 방사성 요오드 섭취 수준의 변화를 관찰하였다. KClO4는 화합물 18a-처리된 세포에서 증진된 방서성 요오드 섭취를 완전히 차단하며 (도 3), 이는 요오드 섭취의 증대가 화합물 18a에 의해 매개된 NIS의 개선된 작용적 활성과 직접 관련됨을 암시한다.After compound 18a treatment, a significant increase in radioactive iodine intake was observed in CAL62 cells according to concentration and time (FIG. 1 and FIG. 2). Maximum increase in iodine intake was observed at the concentration of 12 uM compound 18a. To test whether increased radioactive iodine intake is involved in the regulation of NIS action by compound 18a, a specific inhibitor of NIS, KClO 4, is co-incubated with compound 18a-treated CAL62 cells and radioiodine intake levels The change of was observed. KClO 4 completely blocks enhanced anti-dose iodine intake in compound 18a-treated cells (FIG. 3), suggesting that an increase in iodine intake is directly related to the improved functional activity of NIS mediated by compound 18a .
2.2 ATC 세포에서 화합물 18a에 의한 내생의 ERRγ 와 NIS mRNA 발현 조절2.2 Regulation of Endogenous ERRγ and NIS mRNA Expression by Compound 18a in ATC Cells
ATC 세포에서 ERRγ mRNA 수준에 대한 화합물 18a의 영향을 결정하기 위하여, ERRγ-와 NIS-특이적 프라이머 (Primer)를 이용하여 Real-time PCR을 수행하였다. 화합물 18a를 처리한 결과 CAL62 세포에서 ERRγ mRNA 발현의 현저한 감소가 초래되었고(도 4), 비히클 처리군과 비교 시 약 16배 정도 감소됨을 확인하였다. 반면에 NIS mRNA 발현은 비히클 처리군과 비교했을 때 약 2배정도 증가됨을 확인하였다(도 5).To determine the effect of compound 18a on ERRγ mRNA levels in ATC cells, real-time PCR was performed using ERRγ- and NIS-specific primers. Treatment with Compound 18a resulted in a significant decrease in ERRγ mRNA expression in CAL62 cells (FIG. 4) and a reduction of about 16-fold compared to vehicle treated group. On the other hand, NIS mRNA expression was confirmed to be increased by about two times compared to the vehicle treated group (Fig. 5).
2.3 ATC 세포에서 화합물 18a에 의한 내생의 ERRγ 단백질 발현 조절2.3 Regulation of Endogenous ERRγ Protein Expression by Compound 18a in ATC Cells
ATC 세포에서 ERRγ 단백질 수준에 대한 화합물 18a의 영향을 결정하기 위하여, ERRγ-특이적 항체를 이용하여 면역블롯팅 분석을 수행하였다. 화합물 18a를 처리한 결과 CAL62 세포에서 ERRγ 단백질 발현의 현저한 감소가 초래되었으며(도 6), 비히클 처리군과 비교 시 약 2.8배 정도 감소됨을 확인하였다(도 7).To determine the effect of compound 18a on ERRγ protein levels in ATC cells, immunoblotting assays were performed using ERRγ-specific antibodies. Treatment with Compound 18a resulted in a significant decrease in ERRγ protein expression in CAL62 cells (FIG. 6), and a 2.8-fold reduction compared to the vehicle treatment group (FIG. 7).
2.4 ATC 세포에서 화합물 18a에 의한 내생의 MAP 키나아제 시그널링의 활성화를 통한 ATC 세포에서 막-국재화된(membrane-localized) NIS 단백질의 증가2.4 Increase of membrane-localized NIS protein in ATC cells through activation of endogenous MAP kinase signaling by compound 18a in ATC cells
p44 및 p42 ERK와 같은 포스포릴화된 MAP 키나아제 수준의 현저한 증가가 화합물 18a로 처리된 ATC세포에서 발견되었다(도 8). ERK1 및 ERK2의 포스포릴화된 형태의 상대적 증가는 각각 2.2-배 및 2.8-배였다(도 9).Significant increases in phosphorylated MAP kinase levels such as p44 and p42 ERK were found in ATC cells treated with Compound 18a (FIG. 8). Relative increases in phosphorylated forms of ERK1 and ERK2 were 2.2-fold and 2.8-fold, respectively (Figure 9).
화합물 18a에 의한 방사성요오드 섭취 증가(도 10 및 도 11)와 ERK1 및 ERK2의 포스포릴화된 형태의 상대적 증가는 선택적 MEK 저해제 PD98059, U0126에 의하여 완전히 저해되었다(도 12 및 도 13).Increased radioiodine intake by Compound 18a (FIGS. 10 and 11) and relative increase in phosphorylated forms of ERK1 and ERK2 were completely inhibited by the selective MEK inhibitors PD98059, U0126 (FIGS. 12 and 13).
ATC 세포에서 NIS 단백질 수준에 대한 화합물 18a의 영향을 결정하기 위하여, NIS-특이적 항체를 이용하여 면역블롯팅 분석을 수행하였다. 화합물 18a를 처리한 결과 CAL62 세포에서 total NIS 단백질(fully or partially glycosylated form) 발현의 현저한 증가가 초래되었으며(도 14 및 도 15), 비히클 처리군과 비교시 약 1.9배 정도 감소됨을 확인하였다. NIS 막단백질 상태에 대한 화합물 18a의 효과를 결정하기 위하여, 세포막 비오티닐화 키트를 이용하여 화합물 18a 처리된 CAL62 세포로부터 수집된 막질의(membranous) 총 NIS 단백질의 수준에서의 변화를 NIS-특이적 항체를 이용한 면역블롯팅검사를 이용하여 검사하였다. 화합물 18a는 대조군 세포에 비교하여, ATC 세포에서 성숙 및 미성숙한 형태를 갖는 세포막-국재화된 NIS 단백질의 급격한 증가를 유도하였다(도 14). 밴드 강도의 정량 분석은 CAL62 세포에서 막 fully glycosylated와 partially glycosylated NIS 단백질의 8.1배 및 6.4배 증가를 각각 나타냈다(도 15).To determine the effect of compound 18a on NIS protein levels in ATC cells, immunoblotting assays were performed using NIS-specific antibodies. Treatment with Compound 18a resulted in a significant increase in total NIS protein (fully or partially glycosylated form) expression in CAL62 cells (FIGS. 14 and 15), which was confirmed to be about 1.9-fold reduction compared to vehicle treatment. To determine the effect of compound 18a on NIS membrane protein status, NIS-specific changes in the level of membranous total NIS protein collected from CAL62 cells treated with Compound 18a using a cell membrane biotinylation kit. The test was performed using an immunoblotting test using an antibody. Compound 18a induced a sharp increase in cell membrane-localized NIS protein with mature and immature morphology in ATC cells compared to control cells (FIG. 14). Quantitative analysis of band intensities showed 8.1- and 6.4-fold increases in membrane fully glycosylated and partially glycosylated NIS proteins, respectively, in CAL62 cells (FIG. 15).
2.5 ATC에서 화합물 18a에 의한 I-131 매개된 세포독성의 개량Improvement of I-131 Mediated Cytotoxicity by Compound 18a at 2.5 ATC
I-131 를 이용한 클론형성 분석은 화합물 18a 또는 I-131 단독 중 어느 하나를 이용하여 처리된 CAL62 세포에서 최소의 세포독성 효과를 보였다(도 16). I-131 또는 GSK5182 군의 상대적 콜로니-형성능은 CAL62 세포에서 각각 92.9 ±5.8% 및 94.5 ±10.8% 였다(도 17). 그러나, 131I와 GSK5182의 조합 결과 CAL-62 에서 대략 58.5 ±7.4% 로 콜로니-형성능의 현저한 감소가 일어났다(도 17).Cloning assays using I-131 showed minimal cytotoxic effects in CAL62 cells treated with either Compound 18a or I-131 alone (FIG. 16). The relative colony-forming capacity of the I-131 or GSK5182 groups was 92.9 ± 5.8% and 94.5 ± 10.8% in CAL62 cells, respectively (FIG. 17). However, the combination of 131 I and GSK5182 resulted in a significant reduction in colony-forming capacity of approximately 58.5 ± 7.4% in CAL-62 (FIG. 17).
2.6 ATC 종양모델에서 화합물 18a의 투여에 의한 방사성요오드 섭취 증가2.6 Increased Radioiodine Intake by Administration of Compound 18a in ATC Tumor Models.
CAL62-effluc 마우스 종양모델을 확립한 다음과 같이 그룹을 나누었다(도 18, 그룹 1: Vehicle, 그룹 2: 100mpk 화합물 18a, 그룹 3: 200mpk 화합물 18a). 각 그룹의 마우스들에게 매일 vehicle (100% PEG), 화합물 18a (100mpk, 200 mpk)를 6일 동안 경구투여하였다. 투여 전과 투여 후 종양 성장차이를 모니터링하기 위하여 광학영상 (bioluminescent imaging)을 수행하였다. 약물 마지막 투여 후 다음 날 마우스에 방사성동위원소 (I-125)를 투여하고 2시간 후에 마우스를 희생시킨 후 모든 장기를 적출하여 방사선수치를 감마카운터로 측정하였다. 화합물 18a 처리에 의하여 CAL62 종양내 방사성 요오드 섭취가 농도의존적으로 증가됨을 확인하였다(도 19). 비히클군과 비교 시 100mpk, 200mpk 화합물 18a 군에서 약 4.4배, 16.2 배 방사성요오드 섭취증가를 보였다. 광학영상을 이용하여 종양성장의 차이를 관찰했을 때 화합물 18a 그룹에서 확연한 종양성장 억제효능을 보였다(도 20). 약물 농도의존적으로 종양성장 억제 효능을 보였다(도 21). 마우스의 급격한 체중변화는 모든 그룹에서 나타나지 않았다(도 22).The CAL62-effluc mouse tumor model was established and grouped as follows (FIG. 18, Group 1: Vehicle, Group 2: 100 mpk Compound 18a, Group 3: 200 mpk Compound 18a). Mice in each group were daily orally administered vehicle (100% PEG), compound 18a (100 mpk, 200 mpk) for 6 days. Bioluminescent imaging was performed to monitor tumor growth differences before and after administration. Radioisotope (I-125) was administered to the mice the next day after the last dose of the drug, and after 2 hours, the mice were sacrificed and all organs were removed and the radiation levels were measured by gamma counter. Treatment with Compound 18a confirmed a concentration-dependent increase in radioactive iodine intake in CAL62 tumors (FIG. 19). Compared to the vehicle group, the 100mpk, 200mpk compound 18a group showed an increase of 4.4 times and 16.2 times radioiodine intake. When the difference in tumor growth was observed using optical images, the compound 18a showed a marked tumor growth inhibitory effect (FIG. 20). Drug concentration-dependent tumor growth inhibition effect was shown (Fig. 21). The rapid weight change of mice was not seen in all groups (FIG. 22).
이상에서 본 발명은 기재된 실시예에 대해서만 상세히 기술되었지만, 본 발명의 기술사상 범위 내에서 다양한 변형 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속함은 당연한 것이다.Although the present invention has been described in detail only with respect to the embodiments described, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical spirit of the present invention, and such modifications and modifications belong to the appended claims. .
본 발명의 아릴에텐 유도체는 신규한 화합물로서, 기존의 GSK5182 화합물과 비교하여 ERRγ에 대한 매우 높은 억제 활성을 나타냄과 동시에 약물 안정성, 약리 활성 및 독성이 개선된 효과를 나타내므로, ERRγ에 의해 매개되는 질환, 특히 비만, 당뇨, 고지혈증, 지방간 또는 동맥경화 등과 같은 대사성 질환 뿐만 아니라 망막병증에 대한 효율적인 예방 및 치료제로 부작용없이 유용하게 사용할 수 있다.The arylethene derivative of the present invention is a novel compound, which shows very high inhibitory activity against ERRγ as well as improved drug stability, pharmacological activity and toxicity compared to the existing GSK5182 compound, and thus mediated by ERRγ. As an effective prophylactic and therapeutic agent for retinopathy as well as metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver or arteriosclerosis, etc., it can be usefully used without side effects.
또한, 본 발명의 아릴에텐 유도체는 GSK5182에 비해 ERRγ 전사활성을 특이적으로 현저하게 억제할 수 있으며 그 결과 세포수준에서부터 동물수준에서까지 방사성동위원소 섭취 증가를 유발할 수 있다. 따라서, 암의 치료를 위한 방사성 요오드 요법의 치료 효과를 현저히 증가시킬 수 있으며, 암세포에 투여시 NIS(sodium iodide symporter) 기능이 향상된 암세포를 효과적으로 제조함으로써 미분화 갑상선암 치료를 위한 관련 연구 및 임상에의 적용을 보다 용이하게 할 수 있는 우수한 효과가 있다.In addition, the arylethene derivatives of the present invention can specifically inhibit ERRγ transcriptional activity significantly remarkably compared to GSK5182, and as a result, can increase radioisotope uptake from the cellular level to the animal level. Therefore, it is possible to significantly increase the therapeutic effect of radioactive iodine therapy for the treatment of cancer, and to effectively manufacture cancer cells with enhanced sodium iodide symporter (NIS) function when administered to cancer cells, and to apply them to related studies and clinical applications for the treatment of undifferentiated thyroid cancer. There is an excellent effect that can be made easier.

Claims (12)

  1. 갑상선암 치료용 약제학적 조성물로서, 유효성분으로서 하기 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 약제학적으로 하용 가능한 담체를 포함하고, 방사성 요오드와 병용하여 사용되는 갑상선암 치료용 약제학적 조성물.As a pharmaceutical composition for treating thyroid cancer, an arylethene derivative represented by Formula 1 as an active ingredient, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier A pharmaceutical composition for treating thyroid cancer, the composition comprising a radioactive iodine.
    [화학식 1][Formula 1]
    Figure PCTKR2016010369-appb-I000128
    Figure PCTKR2016010369-appb-I000128
    상기 화학식 1에서, In Chemical Formula 1,
    L은 (C6-C20)아릴렌, (C3-C20)헤테로아릴렌 또는 (C3-C20)융합헤테로고리이고;L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
    R1은 (C3-C20)헤테로사이클로알킬, (C3-C20)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
    R11 내지 R15는 각각 독립적으로 (C3-C20)헤테로사이클로알킬이고; R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl;
    R16 및 R17는 각각 독립적으로 (C1-C20)알킬이고;R 16 and R 17 are each independently (C 1 -C 20) alkyl;
    m은 1 내지 3의 정수이고;m is an integer from 1 to 3;
    n은 0 또는 1의 정수이고;n is an integer of 0 or 1;
    Ar은 (C6-C20)아릴 또는 (C3-C20)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C20)알킬, 할로(C1-C20)알킬, (C1-C20)알콕시, 니트로, 시아노, -NR21R22, (C1-C20)알킬카보닐옥시, (C1-C20)알킬카보닐아미노, 구아니디노, -SO2-R23 및 -OSO2-R24으로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
    R21 및 R22는 각각 독립적으로 수소, (C1-C20)알킬설포닐 또는 (C3-C20)사이클로알킬설포닐이고;R 21 and R 22 are each independently hydrogen, (C 1 -C 20) alkylsulfonyl or (C 3 -C 20) cycloalkylsulfonyl;
    R23 및 R24는 각각 독립적으로 (C1-C20)알킬, 할로(C1-C20)알킬 또는 (C3-C20)사이클로알킬이고;R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
    R2는 히드록시, 할로겐, (C1-C20)알킬카보닐옥시 또는 (C1-C20)알킬설포닐옥시이고;R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
    상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C20)알킬, (C3-C20)사이클로알킬, (C2-C20)알케닐, 아미디노(amidino), (C1-C20)알콕시카보닐, 히드록시, 히드록시(C1-C20)알킬 및 디(C1-C20)알킬아미노(C1-C20)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
    상기 헤테로사이클로알킬 및 헤테로아릴은 N, O 및 S로부터 선택되는 하나 이상의 헤테로 원자를 포함하며, 상기 헤테로사이클로알킬은 고리 내 탄소 원자 또는 질소 원자를 결합 부위로 갖는 포화 또는 불포화된 모노, 바이 또는 스피로 고리이다.The heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
  2. 제 1항에 있어서,The method of claim 1,
    상기 갑상선암은 미분화 갑상선암(analpastic thyroid cancer)인 약제학적 조성물.The thyroid cancer is an undifferentiated thyroid cancer (analpastic thyroid cancer) pharmaceutical composition.
  3. 제 1항에 있어서,The method of claim 1,
    상기 아릴에텐 유도체는 하기 화학식 2 내지 5로 표시되는 아릴에텐 유도체인 약제학적 조성물.The arylethene derivative is a pharmaceutical composition of the arylethene derivative represented by the formula (2 to 5).
    [화학식 2][Formula 2]
    Figure PCTKR2016010369-appb-I000129
    Figure PCTKR2016010369-appb-I000129
    [화학식 3][Formula 3]
    Figure PCTKR2016010369-appb-I000130
    Figure PCTKR2016010369-appb-I000130
    [화학식 4][Formula 4]
    Figure PCTKR2016010369-appb-I000131
    Figure PCTKR2016010369-appb-I000131
    [화학식 5][Formula 5]
    Figure PCTKR2016010369-appb-I000132
    Figure PCTKR2016010369-appb-I000132
    상기 화학식 2 내지 5에서,
    Figure PCTKR2016010369-appb-I000133
    는 단일결합 또는 이중결합을 나타내고; R1, Ar 및 R2는 청구항 제1항에서의 정의와 동일하다.    In Chemical Formulas 2 to 5,
    Figure PCTKR2016010369-appb-I000133
    Represents a single bond or a double bond; R 1 , Ar and R 2 are the same as defined in claim 1.
  4. 제 1항에 있어서,The method of claim 1,
    상기 R1은 (C3-C10)헤테로사이클로알킬, (C3-C10)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R 1 is (C 3 -C 10) heterocycloalkyl, (C 3 -C 10) heteroaryl, —O— (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m- R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
    R11 내지 R15는 각각 독립적으로 (C3-C10)헤테로사이클로알킬이고; R 11 to R 15 are each independently (C 3 -C 10) heterocycloalkyl;
    R16 및 R17는 각각 독립적으로 (C1-C10)알킬이고;R 16 and R 17 are each independently (C 1 -C 10) alkyl;
    m은 1 내지 3의 정수이고;m is an integer from 1 to 3;
    n은 0 또는 1의 정수이고;n is an integer of 0 or 1;
    Ar은 (C6-C12)아릴 또는 (C3-C12)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10 Alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1-C10) alkyl Carbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyloxy or (C3 -C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of;
    R2는 히드록시, 플루오르, (C1-C10)알킬카보닐옥시 또는 (C1-C10)알킬설포닐옥시이고;R 2 is hydroxy, fluorine, (C 1 -C 10) alkylcarbonyloxy or (C 1 -C 10) alkylsulfonyloxy;
    상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있는 것을 특징으로 하는 약제학적 조성물.Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C1-C10) alkoxycarbonyl, hydroxy (C1-C10) alkyl and di (C1-C10) alkylamino (C1-C10) alkyl which may be further substituted with one or more selected from the group consisting of Pharmaceutical compositions.
  5. 제 4항에 있어서,The method of claim 4, wherein
    상기 R1은 (C3-C10)헤테로사이클로알킬 또는 -O-(CH2)m-R11이고, R11은 (C3-C10)헤테로사이클로알킬이고, m은 1 내지 3의 정수이고, 상기 R1 및 R11의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있는 것을 특징으로 하는 약제학적 조성물.R 1 is (C3-C10) heterocycloalkyl or —O— (CH 2 ) m -R 11 , R 11 is (C3-C10) heterocycloalkyl, m is an integer from 1 to 3, and R is Heterocycloalkyl of 1 and R 11 is (C1-C10) alkyl, (C3-C10) cycloalkyl, (C2-C10) alkenyl, amidino, (C1-C10) alkoxycarbonyl, hydroxy ( Pharmaceutical composition, which may be further substituted with one or more selected from the group consisting of C1-C10) alkyl and di (C1-C10) alkylamino (C1-C10) alkyl.
  6. 제 1항에 있어서,The method of claim 1,
    상기 R1 및 R11 내지 R15의 헤테로사이클로알킬은 각각 독립적으로 하기 구조에서 선택되는 것을 특징으로 하는 약제학적 조성물.The heterocycloalkyl of R 1 and R 11 to R 15 are each independently selected from the following structures.
    Figure PCTKR2016010369-appb-I000134
    Figure PCTKR2016010369-appb-I000134
    상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  7. 제 3항에 있어서,The method of claim 3, wherein
    상기 아릴에텐 유도체는 하기 화학식 6으로 표시되는 아릴에텐 유도체인 약제학적 조성물.The arylethene derivative is a pharmaceutical composition of the arylethene derivative represented by the following formula (6).
    [화학식 6][Formula 6]
    Figure PCTKR2016010369-appb-I000135
    Figure PCTKR2016010369-appb-I000135
    상기 화학식 6에서,In Chemical Formula 6,
    R1은 (C3-C10)헤테로사이클로알킬 또는 -O-(CH2)m-R11이고R 1 is (C3-C10) heterocycloalkyl or -O- (CH 2 ) m -R 11
    R11은 (C3-C10)헤테로사이클로알킬이고;R 11 is (C3-C10) heterocycloalkyl;
    m은 1 내지 3의 정수이고; m is an integer from 1 to 3;
    상기 R1 및 R11의 헤테로사이클로알킬은 (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 및 디(C1-C10)알킬아미노(C1-C10)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;The heterocycloalkyl of R 1 and R 11 is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, hydroxide May be further substituted with one or more selected from the group consisting of oxy (C 1 -C 10) alkyl and di (C 1 -C 10) alkylamino (C 1 -C 10) alkyl;
    Ar은 (C6-C12)아릴 또는 (C3-C12)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C10)알킬, 할로(C1-C10)알킬, (C1-C10)알콕시, 니트로, 시아노, 아미노, (C1-C10)알킬설포닐아미노, (C3-C10)시클로알킬설포닐아미노, 디((C1-C10)알킬설포닐)아미노, (C1-C10)알킬카보닐옥시, (C1-C10)알킬카보닐아미노, 구아니디노, (C1-C10)알킬설포닐, (C1-C10)알킬설포닐옥시, 할로(C1-C10)알킬설포닐옥시 또는 (C3-C10)시클로알킬설포닐옥시로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C12) aryl or (C3-C12) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C10) alkyl, halo (C1-C10) alkyl, (C1-C10 Alkoxy, nitro, cyano, amino, (C1-C10) alkylsulfonylamino, (C3-C10) cycloalkylsulfonylamino, di ((C1-C10) alkylsulfonyl) amino, (C1-C10) alkyl Carbonyloxy, (C1-C10) alkylcarbonylamino, guanidino, (C1-C10) alkylsulfonyl, (C1-C10) alkylsulfonyloxy, halo (C1-C10) alkylsulfonyloxy or (C3 -C10) cycloalkylsulfonyloxy and may be further substituted with one or more selected from the group consisting of;
    R2는 히드록시, 플루오르, (C1-C10)알킬카보닐옥시 또는 (C1-C10)알킬설포닐옥시이다.R 2 is hydroxy, fluorine, (C 1 -C 10) alkylcarbonyloxy or (C 1 -C 10) alkylsulfonyloxy.
  8. 제 7항에 있어서,The method of claim 7, wherein
    상기 R2는 히드록시이고, R1은 하기 구조에서 선택되는 헤테로사이클로알킬인 것을 특징으로 하는 약제학적 조성물.Wherein R 2 is hydroxy and R 1 is heterocycloalkyl selected from the following structures.
    Figure PCTKR2016010369-appb-I000136
    Figure PCTKR2016010369-appb-I000136
    상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C3-C10)사이클로알킬, (C2-C10)알케닐, 아미디노(amidino), (C1-C10)알콕시카보닐, 히드록시(C1-C10)알킬 또는 디(C1-C10)알킬아미노(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 10) alkenyl, amidino, (C 1 -C 10) alkoxycarbonyl, Hydroxy (C1-C10) alkyl or di (C1-C10) alkylamino (C1-C10) alkyl; L is O or S.
  9. 제 7항에 있어서,The method of claim 7, wherein
    상기 R2는 히드록시이고, R1은 -O-(CH2)m-R11이고, m은 1 또는 2의 정수이고, R11은 하기 구조에서 선택되는 헤테로사이클로알킬인 것을 특징으로 하는 약제학적 조성물.R 2 is hydroxy, R 1 is -O- (CH 2 ) m -R 11 , m is an integer of 1 or 2, R 11 is a heterocycloalkyl selected from the structure Pharmaceutical composition.
    Figure PCTKR2016010369-appb-I000137
    Figure PCTKR2016010369-appb-I000137
    상기 R31 및 R32는 각각 독립적으로 수소, (C1-C10)알킬, (C1-C10)알콕시카보닐 또는 히드록시(C1-C10)알킬이고; L은 O 또는 S이다.R 31 and R 32 are each independently hydrogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxycarbonyl or hydroxy (C 1 -C 10) alkyl; L is O or S.
  10. 제 3항에 있어서,The method of claim 3, wherein
    상기 아릴에텐 유도체는 하기 구조에서 선택되는 것을 특징으로 하는 약제학적 조성물.The arylethene derivative is a pharmaceutical composition, characterized in that selected from the following structures.
    Figure PCTKR2016010369-appb-I000138
    Figure PCTKR2016010369-appb-I000138
    Figure PCTKR2016010369-appb-I000139
    Figure PCTKR2016010369-appb-I000139
    Figure PCTKR2016010369-appb-I000140
    Figure PCTKR2016010369-appb-I000140
    Figure PCTKR2016010369-appb-I000141
    Figure PCTKR2016010369-appb-I000141
    Figure PCTKR2016010369-appb-I000142
    Figure PCTKR2016010369-appb-I000142
    Figure PCTKR2016010369-appb-I000143
    Figure PCTKR2016010369-appb-I000143
    Figure PCTKR2016010369-appb-I000144
    Figure PCTKR2016010369-appb-I000144
    Figure PCTKR2016010369-appb-I000145
    Figure PCTKR2016010369-appb-I000145
    Figure PCTKR2016010369-appb-I000146
    Figure PCTKR2016010369-appb-I000146
  11. 제 7항에 있어서,The method of claim 7, wherein
    상기 아릴에텐 유도체는 하기 구조에서 선택되는 것을 특징으로 하는 약제학적 조성물.The arylethene derivative is a pharmaceutical composition, characterized in that selected from the following structures.
    Figure PCTKR2016010369-appb-I000147
    Figure PCTKR2016010369-appb-I000147
    Figure PCTKR2016010369-appb-I000148
    Figure PCTKR2016010369-appb-I000148
    Figure PCTKR2016010369-appb-I000149
    Figure PCTKR2016010369-appb-I000149
    Figure PCTKR2016010369-appb-I000150
    Figure PCTKR2016010369-appb-I000150
    Figure PCTKR2016010369-appb-I000151
    Figure PCTKR2016010369-appb-I000151
    Figure PCTKR2016010369-appb-I000152
    Figure PCTKR2016010369-appb-I000152
    Figure PCTKR2016010369-appb-I000153
    Figure PCTKR2016010369-appb-I000153
  12. 하기 화학식 1로 표시되는 아릴에텐 유도체, 그의 프로드럭, 그의 용매화물, 그의 입체이성질체 또는 약제학적으로 허용 가능한 그의 염, 및 방사성 요오드를 포함하는 갑상선암 치료용 키트.A kit for treating thyroid cancer comprising an arylethene derivative represented by Formula 1, a prodrug thereof, a solvate thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a radioactive iodine.
    [화학식 1][Formula 1]
    Figure PCTKR2016010369-appb-I000154
    Figure PCTKR2016010369-appb-I000154
    상기 화학식 1에서, In Chemical Formula 1,
    L은 (C6-C20)아릴렌, (C3-C20)헤테로아릴렌 또는 (C3-C20)융합헤테로고리이고;L is (C6-C20) arylene, (C3-C20) heteroarylene or (C3-C20) fused heterocycle;
    R1은 (C3-C20)헤테로사이클로알킬, (C3-C20)헤테로아릴, -O-(CH2)m-R11, -(CH2)m-R12, -NH-(CH2)m-R13, -NHCO-(CH2)n-R14 또는 -SiR16R17-(CH2)m-R15이고; R 1 is (C3-C20) heterocycloalkyl, (C3-C20) heteroaryl, -O- (CH 2 ) m -R 11 ,-(CH 2 ) m -R 12 , -NH- (CH 2 ) m -R 13 , -NHCO- (CH 2 ) n -R 14 or -SiR 16 R 17- (CH 2 ) m -R 15 ;
    R11 내지 R15는 각각 독립적으로 (C3-C20)헤테로사이클로알킬이고; R 11 to R 15 are each independently (C 3 -C 20) heterocycloalkyl;
    R16 및 R17는 각각 독립적으로 (C1-C20)알킬이고;R 16 and R 17 are each independently (C 1 -C 20) alkyl;
    m은 1 내지 3의 정수이고;m is an integer from 1 to 3;
    n은 0 또는 1의 정수이고;n is an integer of 0 or 1;
    Ar은 (C6-C20)아릴 또는 (C3-C20)헤테로아릴이고, 상기 Ar의 아릴 또는 헤테로아릴은 히드록시, 할로겐, (C1-C20)알킬, 할로(C1-C20)알킬, (C1-C20)알콕시, 니트로, 시아노, -NR21R22, (C1-C20)알킬카보닐옥시, (C1-C20)알킬카보닐아미노, 구아니디노, -SO2-R23 및 -OSO2-R24으로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl of Ar is hydroxy, halogen, (C1-C20) alkyl, halo (C1-C20) alkyl, (C1-C20 Alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20) alkylcarbonyloxy, (C1-C20) alkylcarbonylamino, guanidino, -SO 2 -R 23 and -OSO 2 -R May be further substituted with one or more selected from the group consisting of 24 ;
    R21 및 R22는 각각 독립적으로 수소, (C1-C20)알킬설포닐 또는 (C3-C20)사이클로알킬설포닐이고;R 21 and R 22 are each independently hydrogen, (C 1 -C 20) alkylsulfonyl or (C 3 -C 20) cycloalkylsulfonyl;
    R23 및 R24는 각각 독립적으로 (C1-C20)알킬, 할로(C1-C20)알킬 또는 (C3-C20)사이클로알킬이고;R 23 and R 24 are each independently (C 1 -C 20) alkyl, halo (C 1 -C 20) alkyl or (C 3 -C 20) cycloalkyl;
    R2는 히드록시, 할로겐, (C1-C20)알킬카보닐옥시 또는 (C1-C20)알킬설포닐옥시이고;R 2 is hydroxy, halogen, (C 1 -C 20) alkylcarbonyloxy or (C 1 -C 20) alkylsulfonyloxy;
    상기 R1의 헤테로사이클로알킬 또는 헤테로아릴 및 R11 내지 R15의 헤테로사이클로알킬은 (C1-C20)알킬, (C3-C20)사이클로알킬, (C2-C20)알케닐, 아미디노(amidino), (C1-C20)알콕시카보닐, 히드록시, 히드록시(C1-C20)알킬 및 디(C1-C20)알킬아미노(C1-C20)알킬로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Heterocycloalkyl or heteroaryl of R 1 and heterocycloalkyl of R 11 to R 15 may be selected from (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, amidino, (C1-C20) alkoxycarbonyl, hydroxy, hydroxy (C1-C20) alkyl and di (C1-C20) alkylamino (C1-C20) alkyl, and may be further substituted with one or more selected from the group consisting of;
    상기 헤테로사이클로알킬 및 헤테로아릴은 N, O 및 S로부터 선택되는 하나 이상의 헤테로 원자를 포함하며, 상기 헤테로사이클로알킬은 고리 내 탄소 원자 또는 질소 원자를 결합 부위로 갖는 포화 또는 불포화된 모노, 바이 또는 스피로 고리이다.The heterocycloalkyl and heteroaryl include one or more hetero atoms selected from N, O and S, wherein the heterocycloalkyl is a saturated or unsaturated mono, bi or spiro having a carbon atom or a nitrogen atom in the ring as a bonding site It is a ring.
PCT/KR2016/010369 2016-06-27 2016-09-13 Novel aryl ethane derivative and pharmaceutical composition containing same as active ingredient WO2018004066A1 (en)

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